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1. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author: Winkler, Thomas W., Rasheed, Humaira, Teumer, Alexander, Gorski, Mathias, Rowan, Bryce X., Stanzick, Kira J., Thomas, Laurent F., Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y., Tayo, Bamidele, Thio, Chris H. L., Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B., Horn, Katrin, Li, Man, Scholz, Markus, Cocca, Massimiliano, Wuttke, Matthias, van der Most, Peter J., Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Günther, Felix, Dehghan, Abbas, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P. J., Zonderman, Alan B., Smith, Albert V., Oldehinkel, Albertine J., De Grandi, Alessandro, Rosenkranz, Alexander R., Franke, Andre, Teren, Andrej, Metspalu, Andres, Hicks, Andrew A., Morris, Andrew P., Tönjes, Anke, Morgan, Anna, Podgornaia, Anna I., Peters, Annette, Körner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry I., Spedicati, Beatrice, Ponte, Belen, Schöttker, Ben, Brumpton, Ben, Banas, Bernhard, Krämer, Bernhard K., Jung, Bettina, Åsvold, Bjørn Olav, Smith, Blair H., Ning, Boting, Penninx, Brenda W. J. H., Vanderwerff, Brett R., Psaty, Bruce M., Kammerer, Candace M., Langefeld, Carl D., Hayward, Caroline, Spracklen, Cassandra N., Robinson-Cohen, Cassianne, Hartman, Catharina A., Lindgren, Cecilia M., Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M., Schulz, Christina-Alexandra, Willer, Cristen J., Chasman, Daniel I., Gudbjartsson, Daniel F., Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J., Waterworth, Dawn M., Mascalzoni, Deborah, Mook-Kanamori, Dennis O., Reilly, Dermot F., Daw, E. Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N., Delgado, Graciela E., Montgomery, Grant W., Snieder, Harold, Campbell, Harry, White, Harvey D., Gao, He, Stringham, Heather M., Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holger, Kramer, Holly, Rudan, Igor, Nolte, Ilja M., Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P., Wilson, James F., Halbritter, Jan, Felix, Janine F., Divers, Jasmin, Kooner, Jaspal S., Lee, Jeannette Jen-Mai, O’Connell, Jeffrey, Rotter, Jerome I., Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C., Whitfield, John B., Gaziano, John M., Marten, Jonathan, Coresh, Josef, Jonas, Jost B., Mychaleckyj, Josyf C., Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L., Endlich, Karlhans, Dittrich, Katalin, Ryan, Kathleen A., Rice, Kenneth M., Taylor, Kent D., Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lars, Wallentin, Lars, Yerges-Armstrong, Laura M., Raffield, Laura M., Phillips, Lawrence S., Launer, Lenore J., Lyytikäinen, Leo-Pekka, Lange, Leslie A., Citterio, Lorena, Klaric, Lucija, Ikram, M. Arfan, Ising, Marcus, Kleber, Marcus E., Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Markus, Perola, Markus, de Borst, Martin H., Gögele, Martin, Bianca, Martina La, Lukas, Mary Ann, Feitosa, Mary F., Biggs, Mary L., Wojczynski, Mary K., Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthias, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H., Stumvoll, Michael, Province, Michael A., Evans, Michele K., O’Donoghue, Michelle L., Kubo, Michiaki, Kähönen, Mika, Kastarinen, Mika, Nalls, Mike A., Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G., Tan, Nicholas Y. Q., Palmer, Nicholette D., Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kähönen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T., Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P., Sulem, Patrick, Magnusson, Patrik K. E., Elliott, Paul, Ridker, Paul M., Hamet, Pavel, Svensson, Per O., Joshi, Peter K., Kovacs, Peter, Pramstaller, Peter P., Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z. H., Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Mägi, Reedik, Schmidt, Reinhold, de Mutsert, Renée, Rueedi, Rico, van Dam, Rob M., Carroll, Robert J., Gansevoort, Ron T., Loos, Ruth J. F., Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A., Graham, Sarah E., Gordon, Scott D., Hwang, Shih-Jen, Kerr, Shona M., Vaccargiu, Simona, Patil, Snehal B., Hallan, Stein, Bakker, Stephan J. L., Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S., Lehtimäki, Terho, Boutin, Thibaud S., Meitinger, Thomas, Wong, Tien-Yin, Bergler, Tobias, Rabelink, Ton J., Esko, Tõnu, Haller, Toomas, Thorsteinsdottir, Unnur, Völker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmantas, Gudnason, Vilmundur, Jaddoe, Vincent W. V., Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Hung, Adriana M., Stark, Klaus J., Stefansson, Kari, Böger, Carsten A., Kronenberg, Florian, Köttgen, Anna, Pattaro, Cristian, Heid, Iris M., Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, Research Programs Unit, Tampere University, Clinical Medicine, TAYS Heart Centre, Department of Clinical Chemistry, Department of Clinical Physiology and Nuclear Medicine, Internal Medicine, Pediatrics, Epidemiology, Radiology & Nuclear Medicine, Erasmus MC other, Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), UK DRI Ltd, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Winkler, Thomas W, Rasheed, Humaira, Teumer, Alexander, Gorski, Mathia, Rowan, Bryce X, Stanzick, Kira J, Thomas, Laurent F, Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y, Tayo, Bamidele, Thio, Chris H L, Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B, Horn, Katrin, Li, Man, Scholz, Marku, Cocca, Massimiliano, Wuttke, Matthia, van der Most, Peter J, Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Günther, Felix, Dehghan, Abba, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P J, Zonderman, Alan B, Smith, Albert V, Oldehinkel, Albertine J, De Grandi, Alessandro, Rosenkranz, Alexander R, Franke, Andre, Teren, Andrej, Metspalu, Andre, Hicks, Andrew A, Morris, Andrew P, Tönjes, Anke, Morgan, Anna, Podgornaia, Anna I, Peters, Annette, Körner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry I, Spedicati, Beatrice, Ponte, Belen, Schöttker, Ben, Brumpton, Ben, Banas, Bernhard, Krämer, Bernhard K, Jung, Bettina, Åsvold, Bjørn Olav, Smith, Blair H, Ning, Boting, Penninx, Brenda W J H, Vanderwerff, Brett R, Psaty, Bruce M, Kammerer, Candace M, Langefeld, Carl D, Hayward, Caroline, Spracklen, Cassandra N, Robinson-Cohen, Cassianne, Hartman, Catharina A, Lindgren, Cecilia M, Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M, Schulz, Christina-Alexandra, Willer, Cristen J, Chasman, Daniel I, Gudbjartsson, Daniel F, Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J, Waterworth, Dawn M, Mascalzoni, Deborah, Mook-Kanamori, Dennis O, Reilly, Dermot F, Daw, E Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P, Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N, Delgado, Graciela E, Montgomery, Grant W, Snieder, Harold, Campbell, Harry, White, Harvey D, Gao, He, Stringham, Heather M, Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holgen, Kramer, Holly, Rudan, Igor, Nolte, Ilja M, Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P, Wilson, James F, Halbritter, Jan, Felix, Janine F, Divers, Jasmin, Kooner, Jaspal S, Lee, Jeannette Jen-Mai, O'Connell, Jeffrey, Rotter, Jerome I, Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C, Whitfield, John B, Gaziano, John M, Marten, Jonathan, Coresh, Josef, Jonas, Jost B, Mychaleckyj, Josyf C, Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L, Endlich, Karlhan, Dittrich, Katalin, Ryan, Kathleen A, Rice, Kenneth M, Taylor, Kent D, Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lar, Wallentin, Lar, Yerges-Armstrong, Laura M, Raffield, Laura M, Phillips, Lawrence S, Launer, Lenore J, Lyytikäinen, Leo-Pekka, Lange, Leslie A, Citterio, Lorena, Klaric, Lucija, Ikram, M Arfan, Ising, Marcu, Kleber, Marcus E, Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Marku, Perola, Marku, de Borst, Martin H, Gögele, Martin, Bianca, Martina La, Lukas, Mary Ann, Feitosa, Mary F, Biggs, Mary L, Wojczynski, Mary K, Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthia, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H, Stumvoll, Michael, Province, Michael A, Evans, Michele K, O'Donoghue, Michelle L, Kubo, Michiaki, Kähönen, Mika, Kastarinen, Mika, Nalls, Mike A, Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G, Tan, Nicholas Y Q, Palmer, Nicholette D, Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kähönen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T, Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P, Sulem, Patrick, Magnusson, Patrik K E, Elliott, Paul, Ridker, Paul M, Hamet, Pavel, Svensson, Per O, Joshi, Peter K, Kovacs, Peter, Pramstaller, Peter P, Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z H, Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Mägi, Reedik, Schmidt, Reinhold, de Mutsert, Renée, Rueedi, Rico, van Dam, Rob M, Carroll, Robert J, Gansevoort, Ron T, Loos, Ruth J F, Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A, Graham, Sarah E, Gordon, Scott D, Hwang, Shih-Jen, Kerr, Shona M, Vaccargiu, Simona, Patil, Snehal B, Hallan, Stein, Bakker, Stephan J L, Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S, Lehtimäki, Terho, Boutin, Thibaud S, Meitinger, Thoma, Wong, Tien-Yin, Bergler, Tobia, Rabelink, Ton J, Esko, Tõnu, Haller, Tooma, Thorsteinsdottir, Unnur, Völker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmanta, Gudnason, Vilmundur, Jaddoe, Vincent W V, Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Stark, Klaus J, Stefansson, Kari, Böger, Carsten A, Hung, Adriana M, Kronenberg, Florian, Köttgen, Anna, Pattaro, Cristian, Heid, Iris M, and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: Life Sciences & Biomedicine - Other Topics, EXPRESSION, Diabetic Nephropathies/genetics, 610 Medizin, LOCI, Medicine (miscellaneous), EFFICIENT, Lifelines cohort study, Kidney, General Biochemistry, Genetics and Molecular Biology, DISEASE, QUALITY-CONTROL, SDG 3 - Good Health and Well-being, Diabetic Nephropathy, Diabetes Mellitus, Humans, Medicine [Science], Diabetic Nephropathies, GENOME-WIDE ASSOCIATION, Biology, DiscovEHR/MyCode study, METAANALYSIS, Glomerular Filtration Rate/genetics, Medicinsk genetik, ddc:610, Science & Technology, genetic, effects, kidney, diabetic, JOINT, Klinisk medicin, Diabetes Mellitu, 3126 Surgery, anesthesiology, intensive care, radiology, Multidisciplinary Sciences, ENVIRONMENT INTERACTION, Creatinine, VA Million Veteran Program, Science & Technology - Other Topics, 3111 Biomedicine, Clinical Medicine, SMOKING, General Agricultural and Biological Sciences, Life Sciences & Biomedicine, Medical Genetics, Human, Genome-Wide Association Study, Glomerular Filtration Rate
Abstract: Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM. Published version The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supported the meta-analysis—Project-ID 387509280—SFB1350 (Subproject C6 to I.M.H.). A.M.H., B.R., and R.T. were supported by VACSR&D MVP grant CX001897. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by VACSR&D MVP grant CX001897 (A.M.H.). This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We conducted this research using the UK Biobank resource under the application number 20272.
Published: 2022
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2. Renal function and lipid metabolism are major predictors of circumpapillary retinal nerve fiber layer thickness—the LIFE-Adult Study

Author: Kerstin Wirkner, Thomas Ebert, Christoph Engel, Anke Tönjes, Mike Francke, Mengyu Wang, Tobias Elze, F. Rauscher, Michael Stumvoll, Joachim Thiery, Markus Loeffler, and Peter Stenvinkel
Subjects: Adult, Male, Retinal Ganglion Cells, Oncology, medicine.medical_specialty, Optic Disk, Population, Renal function, Kidney, chemistry.chemical_compound, Nerve Fibers, HDL cholesterol, Internal medicine, eGFR, medicine, Humans, Glucose homeostasis, Cystatin C, education, education.field_of_study, medicine.diagnostic_test, biology, Optical coherence tomography, Cholesterol, business.industry, Glaucoma, General Medicine, Lipid Metabolism, Lipid profile, Retinal nerve fiber layer, chemistry, LDL cholesterol, biology.protein, Medicine, Apolipoprotein A1, Female, Liver function, business, Apolipoprotein B, Biomarkers, Research Article
Abstract: Background Circumpapillary retinal nerve fiber layer thickness (cpRNFLT) as assessed by spectral domain optical coherence tomography (SD-OCT) is a new technique used for the detection and evaluation of glaucoma and other optic neuropathies. Before translating cpRNFLT into clinics, it is crucially important to investigate anthropometric, biochemical, and clinical parameters potentially affecting cpRNFLT in a large population-based dataset. Methods The population-based LIFE-Adult Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. All participants underwent standardized systemic assessment of various cardiometabolic risk markers and ocular imaging, including cpRNFLT measurement using SD-OCT (Spectralis, Heidelberg Engineering). After employing strict SD-OCT quality criteria, 8952 individuals were analyzed. Multivariable linear regression analyses were used to evaluate the independent associations of various cardiometabolic risk markers with sector-specific cpRNFLT. For significant markers, the relative strength of the observed associations was compared to each other to identify the most relevant factors influencing cpRNFLT. In all analyses, the false discovery rate method for multiple comparisons was applied. Results In the entire cohort, female subjects had significantly thicker global and also sectoral cpRNFLT compared to male subjects (p < 0.05). Multivariable linear regression analyses revealed a significant and independent association between global and sectoral cpRNFLT with biomarkers of renal function and lipid profile. Thus, thinner cpRNFLT was associated with worse renal function as assessed by cystatin C and estimated glomerular filtration rate. Furthermore, an adverse lipid profile (i.e., low high-density lipoprotein (HDL) cholesterol, as well as high total, high non-HDL, high low-density lipoprotein cholesterol, and high apolipoprotein B) was independently and statistically significantly related to thicker cpRNFLT. In contrast, we do not observe a significant association between cpRNFLT and markers of inflammation, glucose homeostasis, liver function, blood pressure, or obesity in our sector-specific analysis and globally. Conclusions Markers of renal function and lipid metabolism are predictors of sectoral cpRNFLT in a large and deeply phenotyped population-based study independently of previously established covariates. Future studies on cpRNFLT should include these biomarkers and need to investigate whether incorporation will improve the diagnosis of early eye diseases based on cpRNFLT.
Published: 2021

3. Identification of distinct transcriptome signatures of human adipose tissue from fifteen depots

Author: Peter Kovacs, Dorit Schleinitz, Martin Gericke, Anke Tönjes, Michael Stumvoll, Ingo Bechmann, Kerstin Krause, Matthias Blüher, Nicolas Linder, Claudia Gebhardt, and Tobias Wohland
Subjects: Male, Abdominal Fat, Subcutaneous Fat, Adipose tissue, 030209 endocrinology & metabolism, Inflammation, Biology, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Downregulation and upregulation, Gene expression, Genetics, medicine, Humans, Gene, Genetics (clinical), Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Leptin receptor, Microarray analysis, medicine.disease, Cell biology, Organ Specificity, Female, medicine.symptom, Pericardium
Abstract: The functional and metabolic characteristics of specific adipose tissue (AT) depots seem to be determined by intrinsic mechanisms. We performed a comprehensive transcriptome profiling of human AT from distinct fat depots to unravel their unique features potentially explaining molecular mechanisms underlying AT distribution and their contribution to health and disease. Post-mortem AT samples of five body donors from 15 anatomical locations were collected. Global mRNA expression was measured by Illumina® Human HT-12 v4 Expression BeadChips. Data were validated using qPCR and Western Blot in a subset of ATs from seven additional body donors. Buccal and heel AT clearly separated from the “classical” subcutaneous AT depots, and perirenal and epicardial AT were distinct from visceral depots. Gene-set enrichment analyses pointed to an inflammatory environment and insulin resistance particularly in the carotid sheath AT depot. Moreover, the epicardial fat transcriptome was enriched for genes involved in extracellular matrix remodeling, inflammation, immune signaling, coagulation, thrombosis, beigeing, and apoptosis. Interestingly, a striking downregulation of the expression of leptin receptor was found in AT from heel compared with all other AT depots. The distinct gene expression patterns are likely to define fat depot specific AT functions in metabolism, energy storage, immunity, body insulation or as cushions. Improved knowledge of the gene expression profiles of various fat depots may strongly benefit studies aimed at better understanding of the genetics and the pathophysiology of obesity and adverse body fat composition.
Published: 2020
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4. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Author: Mahmoud Elansary, Knut Krohn, Eleonora Porcu, Julia Dmitrieva, Michel Georges, Harm-Jan Westra, Isabel Alves, Matthias Nauck, Jan H. Veldink, Joost Verlouw, Anette Kalnapenkis, Silva Kasela, Alex W. Hewitt, Roy Oelen, Willem H. Ouwehand, Frank Beutner, Ilkka Seppälä, Yukihide Momozawa, Samuli Ripatti, Brenda W.J.H. Penninx, Patrick Deelen, Michael Stumvoll, Jenny van Dongen, Jonathan K. Pritchard, Roman Kreuzhuber, Marie-Julie Favé, Bernett Lee, Hailang Mei, Biao Zeng, Philip Awadalla, Shuang Li, Kate Downes, Gibran Hemani, Urko M. Marigorta, Anke Tönjes, Morris Swertz, Robert Warmerdam, Joseph E. Powell, Mika Kähönen, Urmo Võsa, Brandon L. Pierce, Benjamin P. Fairfax, Anand Kumar Andiappan, Bastiaan T. Heijmans, Martina Müller-Nurasyid, Sven Bergmann, Katharina Schramm, Hanieh Yaghootkar, Sina Rüeger, Monique G. P. van der Wijst, Lude Franke, Ting Qi, Rick Jansen, Greg Gibson, Cisca Wijmenga, Marc Jan Bonder, Yungil Kim, Viktorija Kukushkina, Johannes Kettunen, Joachim Thiery, Peter A C 't Hoen, Zoltán Kutalik, Jian Yang, Dylan H. de Vries, Olaf Rötzschke, Maarten van Iterson, Peter Kovacs, Peter M. Visscher, Wibowo Arindrarto, Oliver Stegle, Natalia Pervjakova, Julian C. Knight, Tõnu Esko, Annique Claringbould, Lili Milani, Patrick F. Sullivan, Habibul Ahsan, Timothy M. Frayling, Lin Tong, Uwe Völker, Reyhan Sönmez Flitman, Eline Slagboom, Dorret I. Boomsma, Holger Prokisch, Michel G. Nivard, Mawusse Agbessi, Joyce B. J. van Meurs, Alexis Battle, Futao Zhang, Emmanouil T. Dermitzakis, Morris A. Swertz, Grant W. Montgomery, Terho Lehtimäki, Coen D.A. Stehouwer, Jaanika Kronberg, Holger Kirsten, Olli T. Raitakari, Sina A. Gharib, Bruce M. Psaty, Seyhan Yazar, Markus Loeffler, Harm Brugge, Jose Alquicira Hernandez, Mark W. Christiansen, Andrew A. Brown, Markus Perola, Markus Scholz, Ashis Saha, Alexander Teumer, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), BIOS Consortium, i2QTL Consortium, 't Hoen, PAC, van Meurs, J., van Dongen, J., van Iterson, M., Swertz, M.A., Jan Bonder, M., Biological Psychology, APH - Personalized Medicine, APH - Methodology, Internal Medicine, Interne Geneeskunde, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), and RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome
Subjects: DISORDER, Multifactorial Inheritance, Quantitative Trait Loci, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Gene Expression Regulation/genetics, DISEASE, LINKS, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, RELEVANCE, Blood Proteins/genetics, Gene expression, Genetics, Humans, GENOME-WIDE ASSOCIATION, Polymorphism, Gene, Multifactorial Inheritance/genetics, 030304 developmental biology, Regulation of gene expression, RISK, 0303 health sciences, ARCHITECTURE, Blood Proteins, Transcriptome/genetics, Polymorphism, Single Nucleotide/genetics, Phenotype, SERINE BIOSYNTHESIS, HUMAN TRANSCRIPTOME, DEFICIENCY, Gene Expression Regulation, Expression quantitative trait loci, genome-wide association studies, gene expression, gene regulation, Quantitative Trait Loci/genetics, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Single Nucleotide/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.
Published: 2021
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5. (Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution

Author: Anke Tönjes, Peter Kovacs, Matthias Blüher, Annette Horstmann, Torunn Rønningen, Yvonne Böttcher, Kerstin Rohde, Arno Villringer, Michael Stumvoll, Lars la Cour Poulsen, and Maria Keller
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Genotype, Quantitative Trait Loci, Adipose tissue, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Body fat percentage, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Epigenetics, Promoter Regions, Genetic, Alleles, Genetic Association Studies, Adiposity, 2. Zero hunger, Feeding Behavior, General Medicine, DNA Methylation, Middle Aged, medicine.disease, Obesity, Phenotype, 030104 developmental biology, Endocrinology, Adipose Tissue, Gene Expression Regulation, 030220 oncology & carcinogenesis, DNA methylation, Commentary, Female, Three-Factor Eating Questionnaire, Biomarkers, Transcription Factors
Abstract: Background In brain, CREB-regulated transcription co-activator 1 (CRTC1) is involved in metabolic dysregulation. In humans a SNP in CRTC1 was associated to body fat percentage and two SNPs affected RNA Pol II binding and chromatin structure, implying epigenetic regulation of CRTC1. We sought to understand the relevance of CRTC1 SNPs, DNA methylation and expression in human eating behaviour and its relationship to clinical variables of obesity in blood and adipose tissue. Methods 13 CRTC1 SNPs were included to analyze eating behaviour. For rs7256986, follow up association analyses were applied on DNA methylation, CRTC1 expression and clinical parameters. Linear regression was used throughout the study adjusted for age, sex and BMI. Besides data extraction from previous work, rs7256986 was de-novo genotyped and DNA methylation was evaluated by using pyrosequencing. Findings We found several SNPs in the CRTC1 locus nominally associated with human eating behaviour or 2hr postprandial insulin levels and observed a correlation with alcohol and coffee intake (all P
Published: 2019
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6. Circulating Adipokine VASPIN Is Associated with Serum Lipid Profiles in Humans

Author: Beate Gutsmann, Matthias Blüher, Jana Breitfeld, Markus Scholz, Norman Wiele, Peter Kovacs, Anke Tönjes, and Michael Stumvoll
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Apolipoprotein B, Adipokine, Enzyme-Linked Immunosorbent Assay, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Insulin resistance, Adipokines, Internal medicine, medicine, Humans, Obesity, Serpins, Triglycerides, Apolipoproteins B, 030109 nutrition & dietetics, Apolipoprotein A-I, biology, Cholesterol, Organic Chemistry, Lipid metabolism, Cell Biology, Lipoprotein(a), Middle Aged, Lipid Metabolism, medicine.disease, 030104 developmental biology, Endocrinology, chemistry, biology.protein, Female, lipids (amino acids, peptides, and proteins), Apolipoprotein A1, Lipoprotein
Abstract: VASPIN, visceral adipose tissue-derived serpin, is an adipokine ameliorating insulin resistance in obesity. Here, we investigated the role of VASPIN and its genetic variants in lipid metabolism. We measured serum VASPIN concentrations by ELISA in 823 metabolically well-characterized Caucasian subjects (Sorbs from Germany). Furthermore, we genotyped 30 representative single nucleotide polymorphisms (SNP) in two independent cohorts with metabolic phenotyping, the Sorbs (N = 823) and Leipzig (N = 919), and conducted genotype-phenotype association analyses. Circulating VASPIN strongly correlated with triacylglycerol levels (TAG; p = 1.079 × 10-11 ), and moderately with apolipoprotein A1 and low-density lipoprotein cholesterol (p = 0.026). Genetic variants in VASPIN were nominally associated with cholesterol, high-density and low-density lipoprotein (HDL-chol, LDL-chol), lipoprotein A, and apolipoprotein B as well as with TAG and free fatty acids (all p < 0.05 adjusted for age, sex, and body mass index [BMI]). Mendelian randomization analysis using VASPIN SNP as an instrumental variable showed borderline influence of VASPIN on LDL-chol levels (p = 0.05). Associations of VASPIN and its genetic variation with metabolic traits suggest a role of VASPIN in human lipid metabolism.
Published: 2019
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7. Interplay between adipose tissue secreted proteins, eating behavior and obesity

Author: Anke Tönjes, Claudia Gebhard, Peter Kovacs, Markus Scholz, Matthias Blüher, Jana Breitfeld, Marleen Würfel, Michael Stumvoll, Ronny Baber, and Steffi G. Riedel-Heller
Subjects: Adult, Male, medicine.medical_specialty, Hunger, Population, Medicine (miscellaneous), Adipokine, Adipose tissue, Body Mass Index, Internal medicine, medicine, Chemerin, Humans, Obesity, education, education.field_of_study, Nutrition and Dietetics, biology, Adiponectin, business.industry, Leptin, digestive, oral, and skin physiology, Adipokines, Cytokines, Eating Behavior, Feeding Behavior, medicine.disease, Endocrinology, Adipose Tissue, Disinhibition, biology.protein, Female, medicine.symptom, business
Abstract: Purpose Adipokines may play an important role in the complex etiology of human obesity and its metabolic complications. Here, we analyzed the relationship between 15 adipokines, eating behavior and body-mass index (BMI). Methods The study included 557 participants of the Sorbs (62.1% women, 37.9% men) and 3101 participants of the population-based LIFE-Adult cohorts (53.4% women, 46.4% men) who completed the German version of the Three-Factor-Eating Questionnaire to assess the eating behavior types cognitive restraint, disinhibition and hunger. Serum levels of 15 adipokines, including adiponectin, adipocyte fatty acid-binding protein (AFABP), angiopoietin-related growth factor (AGF), chemerin, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, insulin-like growth factor (IGF)-1, interleukin (IL) 10, irisin, progranulin, vaspin, pro-neurotensin (pro-NT), pro-enkephalin (PENK) and leptin were measured. Based on significant correlations between several adipokines with different eating behavior items and BMI, we conducted mediation analyses, considering the eating behavior items as potential mediation variable towards BMI. Results Here, we found that the positive association between chemerin, AFABP or leptin and BMI in Sorbian women was mediated by higher restraint or disinhibited eating, respectively. Additionally, in Sorbian women, the negative relation between IGF-1 and BMI was mediated by higher disinhibition and the positive link between AGF and BMI by lower disinhibition. In Sorbian men, the negative relationship between PENK and BMI was mediated by lower disinhibition and hunger, whereas the negative relation between IGF-1 and BMI was mediated by higher hunger. In the LIFE-Adult women´s cohort, associations between chemerin and BMI were mediated by decreased hunger or disinhibition, respectively, whereas relations between PENK and BMI were fully mediated by decreased disinhibition. Conclusion Our study suggests that adipokines such as PENK, IGF-1, chemerin, AGF, AFABP and leptin might affect the development of obesity by directly modifying individual eating behavior. Given the observational nature of the study, future experimental or mechanistic work is warranted.
Published: 2021
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8. The trans-ancestral genomic architecture of glycemic traits

Author: Albertine J. Oldehinkel, Wieland Kiess, Xueling Sim, Norihiro Kato, Philippe Froguel, Astrid van Hylckama Vlieg, Josée Dupuis, Nanette R. Lee, Symen Ligthart, Harry Campbell, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Massimo Mangino, Tian Xie, Niek Verweij, James B. Meigs, Chaolong Wang, Michael Y. Tsai, Erik Ingelsson, Colin N. A. Palmer, Erik B. van den Akker, Fumihiko Matsuda, Rainer Rauramaa, Yi-Cheng Chang, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Sven Bergmann, Ya X. Wang, Ching-Ti Liu, Annette Schürmann, Michael Boehnke, David J. Porteous, Kazuya Setoh, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Claire J. Steves, Jun Liu, Leslie A. Lange, Noël P. Burtt, Diana Kuh, Cassandra N. Spracklen, Ken K. Ong, Charumathi Sabanayagam, Jost B. Jonas, Ele Ferrannini, Lawrence J. Beilin, Qing Duan, Blair H. Smith, Isobel D. Stewart, Alexander P. Reiner, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Mark I. McCarthy, Anna L. Gloyn, D.I. Boomsma, Dennis Raven, Nicholas J. Timpson, Rona J. Strawbridge, George Dedoussis, Susan Redline, Jaeyoung Hong, Harald Grallert, Jagadish Vangipurapu, Rico Rueedi, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Johannes Waage, Jin Fang Chai, Yii-Der Ida Chen, Graciela E. Delgado, Thibaud S. Boutin, Yang Hai, Yoriko Heianza, Wei Zhao, Andres Metspalu, Tien Yin Wong, Mila Desi Anasanti, Inger Njølstad, Hans Bisgaard, Valeriya Lyssenko, Denis Rybin, Wanqing Wen, Torben Hansen, James F. Wilson, Sameline Grimsgaard, Annette Peters, Michele K. Evans, Damia Noce, Sarah C. Nelson, May E. Montasser, Nan Wang, Geltrude Mingrone, Gudny Eiriksdottir, Nicholas J. Wareham, Fouad Kandeel, Linda S. Adair, Kelvin Lam, Jaana Lindström, Eco J. C. de Geus, Debbie A Lawlor, Sara M. Willems, Xu Lin, Harold Snieder, Matt J. Neville, Naveed Sattar, Chelsea K. Raulerson, Paul M. Ridker, Jer-Yuarn Wu, Weihua Zhang, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Elena Tremoli, Toru Nabika, Jing Hua Zhao, Vilmundur Gudnason, Tao Huang, Robert C. Kaplan, Sohee Han, Mohammad Hadi Zafarmand, Aaron Leong, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Ivana Kolcic, Franco Giulianini, Tao Wang, Lu Qi, Stephan J. L. Bakker, Laura J Corbin, Zoltán Kutalik, Bruna Gigante, Willa A. Hsueh, Peter J. van der Most, Tin Louie, Yujie Wang, Stella Trompet, Fernando Rivideneira, Yasumasa Ohyagi, Lynne E. Wagenknecht, Jerry L. Nadler, Michael Stumvoll, Mark O. Goodarzi, Sahoko Ichihara, Jeffrey R. O'Connell, Tomohiro Katsuya, Giorgio Pistis, Alice Stanton, Sirkka Keinänen-Kiukaanniemi, Momoko Horikoshi, Honglan Li, Tanja G. M. Vrijkotte, Caroline Hayward, Karen L. Mohlke, Carola Marzi, Girish N. Nadkarni, Laura J. Rasmussen-Torvik, Alain G. Bertoni, Andrew R. Wood, Annique Claringbould, Mi Yeong Hwang, Hugh Watkins, Heikki A. Koistinen, Mattias Frånberg, Jani Heikkinen, Elizabeth Selvin, Donald W. Bowden, Abbas Dehghan, Christian Fuchsberger, Audrey Y. Chu, Kent D. Taylor, Katherine A. Kentistou, Johanna Kuusisto, Jingyi Tan, Huaixing Li, Eric Boerwinkle, Catharina A. Hartman, Archie Campbell, Kari E. North, Oluf Pedersen, Sölve Elmståhl, Emil V. R. Appel, Chang-Hsun Hsieh, Dennis O. Mook-Kanamori, Rob M. van Dam, Pontiano Kaleebu, Corri Black, Jennifer A. Brody, Bengt Sennblad, Shaofeng Huo, M. Larissa Avilés-Santa, Ruth J. F. Loos, Patricia B. Munroe, Chien-Hsiun Chen, Liang Sun, Zorayr Arzumanyan, Rebecca Rohde, Yasuharu Tabara, Albert V. Smith, Betina H. Thuesen, Niels Grarup, Jorgen Engmann, Tatijana Zemunik, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Ching-Yu Cheng, Serena Sanna, Damiano Baldassarre, Tarunveer S. Ahluwalia, Mark J. Caulfield, Anne Ndungu, Carl D. Langefeld, Lisa R. Yanek, Luigi Ferrucci, Ananda R. Wickremasinghe, Raymond Noordam, Trevor A. Mori, Tom Wilsgaard, Mika Kivimäki, Rita R. Kalyani, Alan B. Zonderman, Veronique Vitart, Patricia A. Peyser, Shuiqing Lai, Richa Saxena, Li-Ching Chang, Karin Leander, Wei Huang, Peter Vollenweider, Tanya M. Teslovich, Ying Wu, Shufa Du, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Stephen C. J. Parker, Tamar Sofer, Winfried März, Sharon L.R. Kardia, Peter K. Joshi, Neil R. Robertson, Anny H. Xiang, Fumihiko Takeuchi, N. Amin, Jouke-Jan Hottenga, Carol A. Wang, Stefan Gustafsson, Jung Ho Gong, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Gonneke Willemsen, Michael A. Province, Aliki-Eleni Farmaki, Segun Fatumo, Antje Körner, Pim van der Harst, Marie Loh, Kei Hang Katie Chan, Gonçalo R. Abecasis, Nicholette D. Palmer, Simin Liu, Ishminder K. Kooner, Javier Gayán, Arne Astrup, Laura J. Scott, Erwin P. Bottinger, Andrew Wong, Inga Prokopenko, Ping An, Markku Laakso, Matthias Blüher, Susan R. Heckbert, Thomas A. Buchanan, Tatsuaki Matsubara, Andrew P. Morris, Brian H. Chen, Kristi Läll, Teresa Tusie, Timo A. Lakka, Jie Yao, Michael Preuss, Teemu Kuulasmaa, Carlos Lorenzo, Stephen S. Rich, Marie Lauzon, Laura M. Raffield, Pankow S. James, Takahisa Kawaguchi, Kathleen A. Ryan, Wei Zheng, Igor Rudan, Thomas Sparsø, Hugoline G. de Haan, Sandosh Padmanabhan, Richard M. Watanabe, Alicia Huerta-Chagoya, Anette P. Gjesing, Andrew A. Hicks, Richard N. Bergman, Mitsuhiro Yokota, Heather M. Stringham, Bruce M. Psaty, Jian'an Luan, Anuj Goel, Eleanor Wheeler, Masahiro Nakatochi, Young-Jin Kim, Xiao-Ou Shu, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Mari Nelis, Adolfo Correa, Jaspal S. Kooner, Michiya Igase, Anubha Mahajan, Peter E. H. Schwarz, Craig E. Pennell, Claudia Schurmann, Xiaoran Chai, Ji Chen, Lori L. Bonnycastle, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Ilja M. Nolte, Gaëlle Marenne, Timothy M. Frayling, Bong-Jo Kim, Kerrin S. Small, Cecilia M. Lindgren, Bernhard O. Böhm, Shih-Yi Lin, Katharina E. Schraut, Cornelia M. van Duijn, Sanghoon Moon, Mark Walker, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Ko Willems van Dijk, Ozren Polasek, W. Craig Johnson, Dermot F. Reilly, Inês Barroso, Anke Tönjes, Manjinder S. Sandhu, Wen B. Wei, Jose C. Florez, Lorraine Southam, Leif Groop, Lawrence F. Bielak, Peter Kovacs, Jianjun Liu, Jouko Saramies, Helen R. Warren, Man Li, Daniel I. Chasman, Eleftheria Zeggini, Xiaoshuai Zhang, Loic Yengo, Shi Jinxiu, Jirong Long, Xiuqing Guo, Meena Kumari, Leslie J. Raffel, Jill M. Norris, Henrik Vestergaard, Jing He, Peter P. Pramstaller, Diana van Heemst, Kevin Sandow, Marjo-Ritta Jarvelin, Carlos A. Aguilar-Salinas, Peitao Wu, Hortensia Moreno-Macías, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Bernardo L. Horta, Heming Wang, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Rozenn N. Lemaitre, Paul R. H. J. Timmers, Timo Saaristo, Jaakko Tuomilehto, Reedik Mägi, Debashree Ray, J. Wouter Jukema, Claudia Langenberg, Marcus E. Kleber, Francis S. Collins, Klaus Bønnelykke, Lenore J. Launer, Arushi Varshney, Anders Hamsten, European Commission, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanger Institute, Wellcome Trust, Marenne, Gaëlle [0000-0002-4363-7170], Varshney, Arushi [0000-0001-9177-9707], Corbin, Laura J [0000-0002-4032-9500], Parker, Stephen CJ [0000-0001-8122-0117], Langenberg, Claudia [0000-0002-5017-7344], Wheeler, Eleanor [0000-0002-8616-6444], Morris, Andrew P [0000-0002-6805-6014], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Lifelines Cohort Study, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), de Haan, H.G., van den Akker, E., van der Most, P.J., de Geus, EJC, van Dam, R.M., van Heemst, D., van Hylckama Vlieg, A., van Willems van Dijk, K., de Silva, H.J., van der Harst, P., van Duijn, C., Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Helsinki University Hospital Area, University of Helsinki, Clinicum, Department of Public Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Physiology, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, APH - Mental Health, Nutrition and Health, APH - Methodology, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Public and occupational health, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)
Subjects: Blood Glucose, Disease risk, Multifactorial Inheritance, Glycated Hemoglobin A, [SDV]Life Sciences [q-bio], Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), LOCI, Genome-wide association study, Type 2 diabetes, VARIANTS, GLUCOSE, Epigenesis, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Mechanisms, WIDE ASSOCIATION, genetics, Gene-expression, HEMOGLOBIN, ComputingMilieux_MISCELLANEOUS, 11 Medical and Health Sciences, GENE-EXPRESSION, Genetics, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Genome, Loci, 1184 Genetics, developmental biology, physiology, Variants, ALSPAC, Physical Chromosome Mapping, Life Sciences & Biomedicine, Human, Quantitative Trait Loci, Wide association study, Biology, Quantitative trait locus, Article, White People, diseases, MECHANISMS, Quantitative Trait, 03 medical and health sciences, Insulin resistance, Quantitative Trait, Heritable, SDG 3 - Good Health and Well-being, Genetic, Lifelines Cohort Study, Diabetes mellitus, medicine, Humans, Hemoglobin, Heritable, METAANALYSIS, Alleles, 030304 developmental biology, Genetic association, Glycemic, Glycated Hemoglobin, Science & Technology, Genome, Human, Whites, Gene Expression Profiling, DISEASE RISK, Settore MED/13 - ENDOCRINOLOGIA, Insulin-resistance, 06 Biological Sciences, medicine.disease, Glucose, chemistry, Blood Glucose/genetics, European Continental Ancestry Group/genetics, Genome-Wide Association Study, Glycated Hemoglobin A/metabolism, Multifactorial Inheritance/genetics, Quantitative Trait Loci/genetics, Glycated hemoglobin, 030217 neurology & neurosurgery, Meta analysis, Epigenesis, Developmental Biology
Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.
Published: 2021
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9. The Effect of FGF21 and Its Genetic Variants on Food and Drug Cravings, Adipokines and Metabolic Traits

Author: Anke Tönjes, Peter Kovacs, Imke Schamarek, Susan Kralisch, Kerstin Rohde, M Patt, Jana Breitfeld, John T. Heiker, Rima Chakaroun, Sarah Epperlein, Claudia Gebhardt, Michael Stumvoll, and Markus Scholz
Subjects: 0301 basic medicine, medicine.medical_specialty, FGF21, Medicine (miscellaneous), Adipokine, 030209 endocrinology & metabolism, fibroblast growth factor 21, eating behavior, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Internal medicine, Medicine, Chemerin, adipokines, lcsh:QH301-705.5, biology, Adiponectin, business.industry, digestive, oral, and skin physiology, genetic variation in FGF21, addictive behavior, medicine.disease, Obesity, Addictive Behavior, Adipokines, Eating Behavior, Fibroblast Growth Factor 21, Genetic Variation In Fgf21, 030104 developmental biology, Endocrinology, chemistry, lcsh:Biology (General), Cohort, biology.protein, business, Addictive behavior
Abstract: Fibroblast growth factor 21 (FGF21) is a regulator of addictive behavior. Increasing evidence suggests an impact of FGF21 on eating behavior, food and drug cravings and on other adipokines like insulin-like growth factor 1 (IGF-1) or adiponectin. We investigated the association of serum FGF21 and genetic variants with aspects of food and drug craving and obesity related metabolic parameters including serum adipokine levels. Standardized questionnaires, blood samples and anthropometric data of the Sorbs cohort (n = 1046) were analyzed using SPSS. For genetic analyses, the FGF21-locus ±10 kb was genotyped and analyzed using PLINK. Validation was conducted in a second independent cohort (n = 704). FGF21 was significantly associated with alcohol and coffee consumption, smoking and eating behavior (disinhibition). We confirmed correlations of FGF21 serum levels with IGF-1, adiponectin, pro-enkephalin, adipocyte fatty-acid-binding protein, chemerin and progranulin. FGF21 genetic variants were associated with anthropometric and metabolic parameters, adipokines, food and drug craving while strongest evidence was seen with low-density lipoprotein cholesterol (LDL-C). We highlight the potential role of FGF21 in food and drug cravings and provide new insights regarding the link of FGF21 with other adipokines as well as with metabolic traits, in particular those related to lipid metabolism (LDL-C).
Published: 2021

10. Leptin improves parameters of brown adipose tissue thermogenesis in lipodystrophic mice

Author: Ulrike Lossner, Matthias Blüher, Mathias Fasshauer, Mohammed Hankir, Michael Stumvoll, Thomas Ebert, Nora Klöting, Annett Hoffmann, Susan Kralisch, Gesine Flehmig, Konstanze Miehle, Anke Tönjes, and Beate Jessnitzer
Subjects: Leptin, Male, 0301 basic medicine, medicine.medical_specialty, lipodystrophy, Tyrosine 3-Monooxygenase, uncoupling protein 1, Adipose tissue, Adipokine, Mice, Transgenic, 030209 endocrinology & metabolism, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Adipose Tissue, Brown, Internal medicine, Brown adipose tissue, medicine, Animals, TX341-641, ddc:610, sympathetic nervous system, Nutrition and Dietetics, Brown Adipose Tissue, Lipodystrophy, Sympathetic Nervous System, Thermogenesis, Uncoupling Protein 1, Tyrosine hydroxylase, Nutrition. Foods and food supply, brown adipose tissue, medicine.disease, Thermogenin, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Receptors, LDL, Sterol Regulatory Element Binding Protein 1, Food Science
Abstract: Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.
Published: 2021

11. A catalog of genetic loci associated with kidney function from analyses of a million individuals

Author: Wuttke, Matthias, Li, Yong, Li, Man, Sieber, Karsten B., Feitosa, Mary F., Gorski, Mathias, Tin, Adrienne, Wang, Lihua, Chu, Audrey Y., Hoppmann, Anselm, Kirsten, Holger, Giri, Ayush, Chai, Jin-Fang, Sveinbjornsson, Gardar, Tayo, Bamidele O., Nutile, Teresa, Fuchsberger, Christian, Marten, Jonathan, Cocca, Massimiliano, Ghasemi, Sahar, Xu, Yizhe, Horn, Katrin, Noce, Damia, van der Most, Peter J., Sedaghat, Sanaz, Yu, Zhi, Akiyama, Masato, Afaq, Saima, Ahluwalia, Tarunveer S., Almgren, Peter, Amin, Najaf, Ärnlöv, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boehnke, Michael, Boerwinkle, Eric, Boissel, Mathilde, Bottinger, Erwin P., Boutin, Thibaud S., Brenner, Hermann, Brumat, Marco, Burkhardt, Ralph, Butterworth, Adam S., Campana, Eric, Campbell, Archie, Campbell, Harry, Canouil, Mickaël, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Chee, Miao-Ling, Chee, Miao-Li, Chen, Xu, Cheng, Ching-Yu, Cheng, Yurong, Christensen, Kaare, Cifkova, Renata, Ciullo, Marina, Pina Concas, Maria, Cook, James P., Coresh, Josef, Corre, Tanguy, Sala, Cinzia Felicita, Cusi, Daniele, Danesh, John, Daw, E. Warwick, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko P. J., Degenhardt, Frauke, Delgado, Graciela, Demirkan, Ayse, Di Angelantonio, Emanuele, Dittrich, Katalin, Divers, Jasmin, Dorajoo, Rajkumar, Eckardt, Kai-Uwe, Ehret, Georg, Elliott, Paul, Endlich, Karlhans, Evans, Michele K., Felix, Janine F., Foo, Valencia Hui Xian, Franco, Oscar H., Franke, Andre, Freedman, Barry I., Freitag-Wolf, Sandra, Friedlander, Yechiel, Froguel, Philippe, Gansevoort, Ron T., Gao, He, Gasparini, Paolo, Gaziano, J. Michael, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Giulianini, Franco, Gögele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hartman, Catharina A., Hayward, Caroline, Hellwege, Jacklyn N., Heng, Chew-Kiat, Hickst, Andrew A., Hofer, Edith, Huang, Wei, Hutri-Kähönen, Nina, Hwang, Shih-Jen, ikram, M. Arfan, indridason, Olafur S., Ingelsson, Erik, ising, Marcus, Jaddoe, Vincent W. V., Jakobsdottir, Johanna, Jonas, Jost B, Joshi, Peter K., Shilpa Josyula, Navya, Jung, Bettina, Kähönen, Mika, Kamatani, Yoichiro, Kammerer, Candace M., Kanai, Masahiro, Kastarinen, Mika, Kerr, Shona M., Khor, Chiea-Chuen, Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kraja, Aldi T., Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kühnel, Brigitte, Kuokkanen, Mikko, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lange, Leslie A., Langefeld, Carl D., Jen-Mai Lee, Jeannette, Lehne, Benjamin, Lehtimäki, Terho, Lieb, Wolfgang, Cohort Study, Lifelines, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M., Liu, Jun, Liu, Jianjun, Loeffler, Markus, Loos, Ruth J. F., Lucae, Susanne, Ann Lukas, Mary, Lyytikäinen, Leo-Pekka, Mägi, Reedik, Magnusson, Patrik K. 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Subjects: catalog, Inheritance Patterns, Hasso-Plattner-Institut für Digital Engineering GmbH, Genome-wide association study, Disease, Kidney Function Tests, Bioinformatics, DISEASE, 0302 clinical medicine, Uromodulin/urine, kidney function, 11 Medical and Health Sciences, Genetics & Heredity, ddc:616, 0303 health sciences, Kidney, Genome-wide association, HERITABILITY, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, RENAL-FUNCTION, TRANS-EQTLS, METAANALYSIS, TRANSPORTER, CLASSIFICATION, INTEGRATION, Chromosome Mapping, 3. Good health, Phenotype, medicine.anatomical_structure, Medical genetics, Common variants, Renal function, Trans-EQTLS, Metaanalysis, Heritability, Transporter, Life Sciences & Biomedicine, Glomerular Filtration Rate, Metaanalysi, medicine.medical_specialty, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Common variant, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, White People, V. A. Million Veteran Program, 03 medical and health sciences, Quantitative Trait, Heritable, Lifelines Cohort Study, Uromodulin, Genetics, medicine, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, Genetic Association Studies, 030304 developmental biology, Genetic association, Science & Technology, urogenital system, association, genetic loci, 06 Biological Sciences, medicine.disease, Renal Insufficiency, Chronic/genetics/physiopathology/urine, Genetic Association Studies/methods, ddc:000, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study, Kidney disease
Abstract: Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Published: 2019
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12. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences

Author: Karlsson Linnér, Richard, Biroli, Pietro, Kong, Edward, Meddens, S. Fleur W., Wedow, Robbee, Fontana, Mark Alan, Lebreton, Maël, Tino, Stephen P., Abdellaoui, Abdel, Hammerschlag, Anke R., Nivard, Michel G., Okbay, Aysu, Rietveld, Cornelius A., Timshel, Pascal N., Trzaskowski, Maciej, Vlaming, Ronald de, Zünd, Christian L., Bao, Yanchun, Buzdugan, Laura, Caplin, Ann H., Chen, Chia-Yen, Eibich, Peter, Fontanillas, Pierre, Gonzalez, Juan R., Joshi, Peter K., Karhunen, Ville, Kleinman, Aaron, Levin, Remy Z., Lill, Christina M., Meddens, Gerardus A., Muntané, Gerard, Sanchez-Roige, Sandra, Rooij, Frank J. van, Taskesen, Erdogan, Yang, Wu, Zhang, Futao, Agee, Michelle, Alipanahi, Babak, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Furlotte, Nicholas A., Huber, Karen E., Litterman, Nadia K., Mccreight, Jennifer C., Mcintyre, Matthew H., Mountain, Joanna L., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. 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J., Ursano, Robert J., Wagner, Gert G., Adult Psychiatry, APH - Mental Health, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, 23and Me Research Team, eQTLgen Consortium, International Cannabis Consortium, Economics, Biological Psychology, Complex Trait Genetics, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Tinbergen Institute, 23andme Research Team, Psychiatric Genomics Consortium, Social Science Genetic Association Consortium, Linner Richard Karlsson, Biroli P, Kong Edward, Meddens Fleur W., Wedow Robbee, Fontana Mark Alan, Lebreton Mael, Tino Stephen P., Abdellaoui Abdel, Hammerschlag Anke R., Nivard Michel G., Okbay Aysu, Rietveld Cornelius A., Timshel Pascal N., Trzaskowski Maciej, de Vlaming Ronald, Zund Christian L., Bao Yanchun, Buzdugan Laura, Caplin Ann H., Chen Chia-Yen, Eibich Peter, Fontanillas Pierre, Gonzalez Juan R., Joshi Peter K., Karhunen Ville, Kleinman Aaron, Levin Remy Z., Lill Christina M., Meddens Gerardus A., Muntane Gerard, Sanchez-Roige Sandra, van Rooij Frank J., Taskesen Erdogan, Wu Yang, Zhang Futao, Agee Michelle, Alipanahi Babak, Bell Robert K., Bryc Katarzyna, Elson Sarah L., Furlotte Nicholas A., Huber Karen E., Litterman Nadia K., McCreight Jennifer C., McIntyre Matthew H., Mountain Joanna L., Northover Carrie A. M., Pitts Steven J., Sathirapongsasuti J. Fah, Sazonova Olga V., Shelton Janie F., Shringarpure Suyash, Tian Chao, Tung Joyce Y., Vacic Vladimir, Wilson Catherine H., Agbessi Mawusse, Ahsan Habibul, Alves Isabel, Andiappan Anand, Awadalla Philip, Battle Alexi, Beutner Frank, Bonder Marc Jan, Boomsma Dorret I., Christiansen Mark, Claringbould Annique, Deelen Patrick, Esko Tonu, Fave Marie-Julie, Franke Lude, Frayling Timothy, Gharib Sina A., Gibson Gregory, Heijmans Bastiaan, Hemani Gibran, Jansen Rick, Kahonen Mika, Kalnapenkis Anette, Kasela Silva, Kettunen Johanne, Kim Yungil, Kirsten Holger, Kovacs Peter, Krohn Knut, Kronberg-Guzman Jaanika, Kukushkina Viktorija, Kutalik Zoltan, Lee Bernett, Lehtimaki Terho, Loeffler Marku, Marigorta Urko M., Metspalu Andre, Milani Lili, Montgomery Grant W., Mueller-Nurasyid Martina, Nauck Matthia, Penninx Brenda, Perola Marku, Pervjakova Natalia, Pierce Brandon, Powell Joseph, Prokisch Holger, Psaty Bruce M., Raitakari Olli, Ring Susan, Ripatti Samuli, Rotzchke Olaf, Rueger Sina, Saha Ashi, Scholz Marku, Schramm Katharina, Seppala Ilkka, Stumvoll Michael, Sullivan Patrick, Hoen Peter-Bramt, Teumer Alexander, Thiery Joachim, Tong Lin, Tonjes Anke, van Dongen Jenny, van Meurs Joyce, Verlouw Joost, Visscher Peter M., Voelker Uwe, Vosa Urmo, Westra Harm-Jan, Yaghootkar Hanieh, Yang Jian, Zeng Biao, Lee James J., Pers Tune H., Turley Patrick, Chen Guo-Bo, Emilsson Valur, Oskarsson Sven, Pickrell Joseph K., Thom Kevin, Timshel Pascal, Ahluwalia Tarunveer S., Bacelis Jona, Baumbach Clemen, Bjornsdottir Gyda, Brandsma Johannes H., Concas Maria Pina, Derringer Jaime, Galesloot Tessel E., Girotto Giorgia, Gupta Richa, Hall Leanne M., Harris Sarah E., Hofer Edith, Horikoshi Momoko, Huffman Jennifer E., Kaasik Kadri, Kalafati Ioanna P., Kong Augustine, Lahti Jari, van der Lee Sven J., de Leeuw Christiaan, Lind Penelope A., Lindgren Karl-Oskar, Liu Tian, Mangino Massimo, Marten Jonathan, Mihailov Evelin, Miller Michael B., van der Most Peter J., Oldmeadow Christopher, Payton Antony, Peyrot Wouter J., Qian Yong, Rueedi Rico, Salvi Erika, Schmidt Boerge, Schraut Katharina E., Shi Jianxin, Smith Albert V., Poot Raymond A., St Pourcain Beate, Thorleifsson Gudmar, Verweij Niek, Vuckovic Dragana, Wellmann Juergen, Yang Jingyun, Zhao Wei, Zhu Zhihong, Alizadeh Behrooz Z., Amin Najaf, Bakshi Andrew, Baumeister Sebastian E., Biino Ginevra, Bonnelykke Klau, Boyle Patricia A., Campbell Harry, Cappuccio Francesco P., Davies Gail, De Neve Jan-Emmanuel, Deloukas Pano, Demuth Ilja, Ding Jun, Eisele Lewin, Eklund Niina, Evans David M., Faul Jessica D., Feitosa Mary F., Forstner Andreas J., Gandin Ilaria, Gunnarsson Bjarni, Halldorsson Bjarni V., Harris Tamara B., Heath Andrew C., Hocking Lynne J., Holliday Elizabeth G., Homuth Georg, Horan Michael A., Hottenga Jouke-Jan, de Jager Philip L., Jugessur Astanand, Kaakinen Marika A., Kanoni Stavroula, Keltigangas-Jarvinen Liisa, Kiemeney Lambertus A. L. M., Kolcic Ivana, Koskinen Seppo, Kraja Aldi T., Kroh Martin, Latvala Antti, Launer Lenore J., Lebreton Mael P., Levinson Douglas F., Lichtenstein Paul, Lichtner Peter, Liewald David C. M., Loukola Anu, Madden Pamela A., Magi Reedik, Maki-Opas Tomi, Marioni Riccardo E., Marques-Vidal Pedro, McMahon George, Meisinger Christa, Meitinger Thoma, Milaneschi Yusplitri, Myhre Ronny, Nelson Christopher P., Nyholt Dale R., Ollier William E. R., Palotie Aarno, Paternoster Lavinia, Pedersen Nancy L., Petrovic Katja E., Porteous David J., Raikkonen Katri, Ring Susan M., Robino Antonietta, Rostapshova Olga, Rudan Igor, Rustichini Aldo, Salomaa Veikko, Sanders Alan R., Sarin Antti-Pekka, Schmidt Helena, Scott Rodney J., Smith Blair H., Smith Jennifer A., Staessen Jan A., Steinhagen-Thiessen Elisabeth, Strauch Konstantin, Terracciano Antonio, Tobin Martin D., Ulivi Sheila, Vaccargiu Simona, Quaye Lydia, Venturini Cristina, Vinkhuyzen Anna A. E., Voelzke Henry, Vonk Judith M., Vozzi Diego, Waage Johanne, Ware Erin B., Willemsen Gonneke, Attia John R., Bennett David A., Berger Klau, Bertram Lar, Bisgaard Han, Borecki Ingrid B., Bultmann Ute, Chabris Christopher F., Cucca Francesco, Cusi Daniele, Deary J., Dedoussis George V., van Duijn Cornelia M., Eriksson Johan G., Franke Barbara, Gasparini Paolo, Gejman Pablo V., Gieger Christian, Grabe Hans-Joergen, Gratten Jacob, Gudnason Vilmundur, van der Harst Pim, Hayward Caroline, Hinds David A., Hoffmann Wolfgang, Hypponen Elina, Iacono William G., Jacobsson Bo, Jarvelin Marjo-Riitta, Jockel Karl-Heinz, Kaprio Jaakko, Kardia Sharon L. R., Lehrer Steven F., Magnusson Patrik K. E., Martin Nicholas G., McGue Matt, Pendleton Neil, Pirastu Nicola, Pirastu Mario, Polasek Ozren, Posthuma Danielle, Power Christine, Province Michael A., Samani Nilesh J., Schlessinger David, Schmidt Reinhold, Sorensen Thorkild I. A., Spector Tim D., Stefansson Kari, Thorsteinsdottir Unnur, Thurik A. Roy, Timpson Nicholas J., Tiemeier Henning, Uitterlinden Andre G., Vitart Veronique, Vollenweider Peter, Weir David R., Wilson James F., Wright Alan F., Conley Dalton C., Krueger Robert F., Smith George Davey, Laibson David I., Medland Sarah E., Johannesson Magnu, Koellinger Philipp D., Cesarini David, Benjamin Daniel J., Auton Adam, Boardman Jason D., Clark David W., Conlin Andrew, Dolan Conor C., Fischbacher Ur, Groenen Patrick J. F., Harris Kathleen Mullan, Hasler Gregor, Hofman Albert, Ikram Mohammad A., Jain Sonia, Karlsson Robert, Kessler Ronald C., Kooyman Maarten, MacKillop Jame, Mannikko Minna, Morcillo-Suarez Carlo, McQueen Matthew B., Schmidt Klaus M., Smart Melissa C., Sutter Matthia, White Jon, de Wit Harriet, Fehr Ernst, Kumari Meena, Laibson David, Meyer Michelle N., Navarro Arcadi, Palmer Abraham A., Schunk Daniel, Stein Murray B., Svento Rauli, Timmers Paul R. H. J., Ursano Robert J., Wagner Gert G., Beauchamp Jonathan P., Karlsson Linnér, Richard, Biroli, Pietro, Kong, Edward, Meddens, S. Fleur W., Wedow, Robbee, Fontana, Mark Alan, Lebreton, Maël, Tino, Stephen P., Abdellaoui, Abdel, Hammerschlag, Anke R., Nivard, Michel G., Okbay, Aysu, Rietveld, Cornelius A., Timshel, Pascal N., Trzaskowski, Maciej, Vlaming, Ronald de, Zünd, Christian L., Bao, Yanchun, Buzdugan, Laura, Caplin, Ann H., Chen, Chia-Yen, Eibich, Peter, Fontanillas, Pierre, Gonzalez, Juan R., Joshi, Peter K., Karhunen, Ville, Kleinman, Aaron, Levin, Remy Z., Lill, Christina M., Meddens, Gerardus A., Muntané, Gerard, Sanchez-Roige, Sandra, Rooij, Frank J. van, Taskesen, Erdogan, Wu, Yang, Zhang, Futao, Agee, Michelle, Alipanahi, Babak, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Furlotte, Nicholas A., Huber, Karen E., Litterman, Nadia K., Mccreight, Jennifer C., Mcintyre, Matthew H., Mountain, Joanna L., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand, Awadalla, Philip, Battle, Alexi, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark, Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Gregory, Heijmans, Bastiaan, Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johanne, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg-Guzman, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Marku, Marigorta, Urko M., Metspalu, Andre, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthia, Penninx, Brenda, Perola, Marku, Pervjakova, Natalia, Pierce, Brandon, Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli, Ring, Susan, Ripatti, Samuli, Rotzchke, Olaf, Rüeger, Sina, Saha, Ashi, Scholz, Marku, Schramm, Katharina, Seppälä, Ilkka, Stumvoll, Michael, Sullivan, Patrick, Hoen, Peter-Bram t, Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, Dongen, Jenny van, Meurs, Joyce van, Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Beauchamp, Jonathan P., Lee, James J., Pers, Tune H., Turley, Patrick, Chen, Guo-Bo, Emilsson, Valur, Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, de Vlaming, Ronald, Ahluwalia, Tarunveer S., Bacelis, Jona, Baumbach, Clemen, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, Maria Pina, Derringer, Jaime, Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, Lee, Sven J. van der, de Leeuw, Christiaan, Lind, Penelope A., Lindgren, Karl-Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., Most, Peter J. van der, Oldmeadow, Christopher, Payton, Antony, Peyrot, Wouter J., Qian, Yong, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., Pourcain, Beate St, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klau, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan-Emmanuel, Deloukas, Pano, Demuth, Ilja, Ding, Jun, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Heath, Andrew C., Hocking, Lynne J., Holliday, Elizabeth G., Homuth, Georg, Horan, Michael A., Hottenga, Jouke-Jan, de Jager, Philip L., Jugessur, Astanand, Kaakinen, Marika A., Kanoni, Stavroula, Keltigangas-Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, Anu, Madden, Pamela A., Mägi, Reedik, Mäki-Opas, Tomi, Marioni, Riccardo E., Marques-Vidal, Pedro, Mcmahon, George, Meisinger, Christa, Meitinger, Thoma, Milaneschi, Yusplitri, Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Räikkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti-Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen-Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, Venturini, Cristina, Vinkhuyzen, Anna A. E., Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johanne, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klau, Bertram, Lar, Bisgaard, Han, Borecki, Ingrid B, Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., Duijn, Cornelia M. van, Eriksson, Johan G., Franke, Barbara, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans-Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, Harst, Pim van der, Hayward, Caroline, Hinds, David A., Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Pendleton, Neil, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Smith, George Davey, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Johannesson, Magnu, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., Auton, Adam, Boardman, Jason D., Clark, David W., Conlin, Andrew, Dolan, Conor C., Fischbacher, Ur, Harris, Kathleen Mullan, Hasler, Gregor, Ikram, Mohammad A., Jain, Sonia, Kessler, Ronald C., Kooyman, Maarten, Mackillop, Jame, Männikkö, Minna, Morcillo-Suarez, Carlo, Mcqueen, Matthew B., Schmidt, Klaus M., Smart, Melissa C., Sutter, Matthia, White, Jon, Wit, Harriet de, Fehr, Ernst, Kumari, Meena, Laibson, David, Navarro, Arcadi, Palmer, Abraham A., Schunk, Daniel, Stein, Murray B., Svento, Rauli, Timmers, Paul R. H. J., Ursano, Robert J., Wagner, Gert G., Applied Economics, Hematology, Epidemiology, Urology, Department of Marketing Management, Internal Medicine, Medical Informatics, Cell biology, Erasmus MC other, Molecular Genetics, Econometrics, Child and Adolescent Psychiatry / Psychology, Radiology & Nuclear Medicine, Epidemiologie, RS: CARIM - R3.02 - Hypertension and target organ damage, RS: Carim - V02 Hypertension and target organ damage, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Public Health Research (PHR), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Linnér, Richard Karlsson, Biroli , Pietro, Meddens, S Fleur W, and Beauchamp, Jonathan P
Subjects: Netherlands Twin Register (NTR), Male, LD, Medizin, Poison control, Genome-wide association study, DETERMINANTS, Cathie Marsh Institute, PREFERENCES, Q1, Genome-wide association studies, HV, 0302 clinical medicine, Genetics, Behavioral/methods, GWAS, Genetics & Heredity, Genetics, 0303 health sciences, PERSONALITY, Genetic Predisposition to Disease/genetics, Behavior/physiology, Polymorphism, Single Nucleotide/genetics, 3. Good health, Manchester Institute for Collaborative Research on Ageing, Meta-analysis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Genetic Loci/genetics, Behavioural genetics, Genome-Wide Association Study/methods, Medical genetics, Female, Life Sciences & Biomedicine, Single Nucleotide/genetics, medicine.medical_specialty, ResearchInstitutes_Networks_Beacons/MICRA, Genotype, Single-nucleotide polymorphism, Genetics, Behavioral, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, ddc:330, medicine, GENDER-DIFFERENCES, SNP, Humans, Genetic Predisposition to Disease, Polymorphism, behavioural genetics, Behavioral/methods, 030304 developmental biology, Genetic association, Behavior, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Data Science, Case-control study, risk tolerance, GWAS, genetic architechture, Genetic Loci, Case-Control Studies, genome-wide association studies, ResearchInstitutes_Networks_Beacons/cathie_marsh_institute, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance. This research was carried out under the auspices of the Social Science Genetic Association Consortium. The research was also conducted using the UK Biobank Resource under application number 11425. The study was supported by funding from the Ragnar Söderberg Foundation (E9/11 and E42/15); the Swedish Research Council (421-2013-1061); the Jan Wallander and Tom Hedelius Foundation; an ERC Consolidator Grant to Philipp Koellinger (647648 EdGe); the Pershing Square Fund of the Foundations of Human Behavior; the Open Philanthropy Project; the National Institute on Aging, National Institutes of Health through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to the National Bureau of Economic Research and R01-AG042568-02 to the University of Southern California; the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-152); and the Social Sciences and Humanities Research Council of Canada. We thank the International Cannabis Consortium, the eQTLgen Consortium, and the Psychiatric Genomics Consortium for sharing summary statistics from the GWAS of lifetime cannabis use, eQTL summary statistics, and summary statistics from the GWAS of ADHD, respectively. A full list of acknowledgments is provided in the Supplementary Note.
Published: 2019
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13. Refining Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Genetic Loci by Integrating Summary Data From Genome-wide Association, Gene Expression, and DNA Methylation Studies

Author: Anke R. Hammerschlag, Enda M. Byrne, Meike Bartels, Naomi R. Wray, Christel M. Middeldorp, Mawussé Agbessi, Habibul Ahsan, Isabel Alves, Anand Andiappan, Wibowo Arindrarto, Philip Awadalla, Alexis Battle, Frank Beutner, Marc Jan Bonder, Dorret I. Boomsma, Mark Christiansen, Annique Claringbould, Patrick Deelen, Tõnu Esko, Marie-Julie Favé, Lude Franke, Timothy Frayling, Sina A. Gharib, Gregory Gibson, Bastiaan T. Heijmans, Gibran Hemani, Rick Jansen, Mika Kähönen, Anette Kalnapenkis, Silva Kasela, Johannes Kettunen, Yungil Kim, Holger Kirsten, Peter Kovacs, Knut Krohn, Jaanika Kronberg-Guzman, Viktorija Kukushkina, Zoltan Kutalik, Bernett Lee, Terho Lehtimäki, Markus Loeffler, Urko M. Marigorta, Hailang Mei, Lili Milani, Grant W. Montgomery, Martina Müller-Nurasyid, Matthias Nauck, Michel Nivard, Brenda Penninx, Markus Perola, Natalia Pervjakova, Brandon L. Pierce, Joseph Powell, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Samuli Ripatti, Olaf Rotzschke, Sina Rüeger, Ashis Saha, Markus Scholz, Katharina Schramm, Ilkka Seppälä, Eline P. Slagboom, Coen D.A. Stehouwer, Michael Stumvoll, Patrick Sullivan, Peter A.C. ‘t Hoen, Alexander Teumer, Joachim Thiery, Lin Tong, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Joyce van Meurs, Jan H. Veldink, Joost Verlouw, Peter M. Visscher, Uwe Völker, Urmo Võsa, Harm-Jan Westra, Cisca Wijmenga, Hanieh Yaghootkar, Jian Yang, Biao Zeng, Futao Zhang, Aaron Isaacs, René Pool, Jouke J. Hottenga, Marleen MJ. van Greevenbroek, Carla J.H. van der Kallen, Casper G. Schalkwijk, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana van Heemst, Leonard H. van den Berg, Cornelia M. van Duijn, Bert A. Hofman, André G. Uitterlinden, P. Mila Jhamai, Michael Verbiest, H.Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Michiel van Galen, Jan Bot, Daria V. Zhernakova, Peter van ‘t Hof, Irene Nooren, Matthijs Moed, Martijn Vermaat, René Luijk, Freerk van Dijk, Szymon M. Kielbasa, Morris A. Swertz, Erik. W. van Zwet, Peter-Bram ‘t Hoen, MUMC+: Centrum voor Chronische Zieken (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, MUMC+: HVC Pieken Maastricht Studie (9), Interne Geneeskunde, MUMC+: MA Interne Geneeskunde (3), Urology, Medical Informatics, Department of Marketing Management, Epidemiology, Internal Medicine, Dermatology, Ophthalmology, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, VU University medical center, Clinical chemistry, Human genetics, APH - Digital Health, APH - Methodology, Biological Psychology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: 0301 basic medicine, Candidate gene, mQTL, Autism Spectrum Disorder, Gene Expression, Genome-wide association study, Biology, Quantitative trait locus, VARIANTS, eQTL, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, mental disorders, Humans, GWAS, BRAIN, Biological Psychiatry, Genetic association, Genetics, Regulation of gene expression, Pleiotropy, HERITABILITY, dNaM, DNA Methylation, SMR, Fetal brain, PREVALENCE, 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, DNA methylation, 17Q21.31, Psychiatric disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BACKGROUND: Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels.METHODS: We applied summary-data-based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data-based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels.RESULTS: We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before.CONCLUSIONS: Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies.
Published: 2020
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14. Genetically programmed changes in transcription of the novel progranulin regulator

Author: Maria Keller, Michael Stumvoll, S. Huth, Peter Kovacs, Markus Scholz, Henrike O. Heyne, Dorit Schleinitz, Claudia Gebhardt, Anke Tönjes, and Yvonne Böttcher
Subjects: Adult, Male, Progranulin, Genotype, Transcription, Genetic, Biology, EMSA, Polymorphism, Single Nucleotide, Cell Line, Epigenesis, Genetic, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Progranulins, Transcription (biology), Genes, Reporter, Drug Discovery, Humans, Luciferase, RNA, Messenger, Allele, Transcription factor, Genetics (clinical), Alleles, Phylogeny, YY1 Transcription Factor, 030304 developmental biology, Aged, 0303 health sciences, DNA methylation, PSRC1, Genetic Variation, Promoter, Middle Aged, Molecular biology, Psrc1, Dna Methylation, Emsa, DNA binding site, chemistry, Gene Expression Regulation, 030220 oncology & carcinogenesis, Molecular Medicine, Original Article, Female, DNA, Protein Binding
Abstract: Abstract Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P −7) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 × 10−3). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P −7). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. Key messages PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels. rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding. PSRC1 is also epigenetically regulated in subjects with high progranulin levels.
Published: 2020

15. Relationship Between 12 Adipocytokines and Distinct Components of the Metabolic Syndrome

Author: Dorit Schleinitz, Claudia Gebhardt, Tobias Wohland, Matthias Blüher, Mathias Fasshauer, Markus Scholz, Michael Stumvoll, Thomas Ebert, Anke Tönjes, and Peter Kovacs
Subjects: Male, 0301 basic medicine, FGF21, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Adipose tissue, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Germany, Adipocyte, Ethnicity, Cluster Analysis, Medicine, Metabolic Syndrome, education.field_of_study, biology, Middle Aged, Adipose Tissue, Intercellular Signaling Peptides and Proteins, Female, Adiponectin, Chemokines, Adult, medicine.medical_specialty, Population, Adipokine, 030209 endocrinology & metabolism, Fatty Acid-Binding Proteins, 03 medical and health sciences, Adipokines, Internal medicine, Humans, Chemerin, education, business.industry, Biochemistry (medical), medicine.disease, Fibroblast Growth Factors, Fibroblast Growth Factor-23, Cross-Sectional Studies, 030104 developmental biology, chemistry, Multivariate Analysis, Linear Models, biology.protein, Metabolic syndrome, business, Biomarkers
Abstract: Objective Adipose tissue–derived signals potentially link obesity and adipose tissue dysfunction with metabolic and cardiovascular diseases. Although some adipocytokines have been closely related to metabolic and cardiovascular traits, it is unknown which adipocytokine or adipocytokine clusters serve as meaningful markers of metabolic syndrome (MS) components. Therefore, this study investigated the associations of 12 adipocytokines with components of the MS to identify the most relevant cytokines potentially related to specific metabolic profiles. Research Design and Methods Twelve cytokines [adiponectin, adipocyte fatty acid–binding protein (AFABP), angiopoietin-related growth factor, chemerin, fibroblast growth factor (FGF) 19, FGF21, FGF23, insulin-like growth factor-1, interleukin 10, irisin, progranulin, and vaspin] were quantified in a cross-sectional cohort of 1046 subjects. Hypothesis-free cluster analysis, multivariate regression analyses with parameters of the MS, and discriminant analysis were performed to assess associations and the relative importance of each cytokine for reflecting MS and its components. Results Among the studied adipocytokines, adiponectin, AFABP, chemerin, and FGF21 showed the strongest associations with MS and several MS components in discriminant analyses and multiple regression models. For certain metabolic components, these adipocytokines were better discriminators than routine metabolic markers. Other cytokines investigated in the present cohort are less able to distinguish between metabolically healthy and unhealthy subjects. Conclusions Adiponectin, AFABP, chemerin, and FGF21 showed the strongest associations with MS components in a general population, suggesting that adverse adipose tissue function is a major contributor to these metabolic abnormalities. Future prospective studies should address the question whether these adipocytokines can predict the development of metabolic disease states.
Published: 2018
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16. Quality control and conduct of genome-wide association meta-analyses

Author: Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis GR, Absher D, Alavere H, Albrecht E, Allen HL, Almgren P, Amin N, Amouyel P, Anderson D, Arnold AM, Arveiler D, Aspelund T, Asselbergs FW, Assimes TL, Atalay M, Attwood AP, Atwood LD, Bakker SJ, Balkau B, Balmforth AJ, Barlassina C, Barroso I, Basart H, Bauer S, Beckmann JS, Beilby JP, Bennett AJ, Ben Shlomo Y, Bergman RN, Bergmann S, Berndt SI, Biffar R, Di Blasio AM, Boehm BO, Boehnke M, Boeing H, Boerwinkle E, Bolton JL, Bonnefond A, Bonnycastle LL, Boomsma DI, Borecki IB, Bornstein SR, Bouatia Naji N, Boucher G, Bragg Gresham JL, BRAMBILLA, PAOLO, Bruinenberg M, Buchanan TA, Buechler C, Cadby G, Campbell H, Caulfield MJ, Cavalcanti Proença C, CESANA, GIANCARLO, Chanock SJ, Chasman DI, Chen YD, Chines PS, Clegg DJ, Coin L, Collins FS, Connell JM, Cookson W, Cooper MN, Croteau Chonka DC, Cupples LA, Cusi D, Day FR, Day IN, Dedoussis GV, Dei M, Deloukas P, Dermitzakis ET, Dimas AS, Dimitriou M, Dixon AL, Dörr M, van Duijn CM, Ebrahim S, Edkins S, Eiriksdottir G, Eisinger K, Eklund N, Elliott P, Erbel R, Erdmann J, Erdos MR, Eriksson JG, Esko T, Estrada K, Evans DM, de Faire U, Fall T, Farrall M, Feitosa MF, Ferrario MM, Ferreira T, Ferrières J, Fischer K, Fisher E, Fowkes G, Fox CS, Franke L, Franks PW, Fraser RM, Frau F, Frayling T, Freimer NB, Froguel P, Fu M, Gaget S, Ganna A, Gejman PV, Gentilini D, Geus EJ, Gieger C, Gigante B, Gjesing AP, Glazer NL, Goddard ME, Goel A, Grallert H, Gräßler J, Grönberg H, Groop LC, Groves CJ, Gudnason V, Guiducci C, Gustafsson S, Gyllensten U, Hall AS, Hall P, Hallmans G, Hamsten A, Hansen T, Haritunians T, Harris TB, van der Harst P, Hartikainen AL, Hassanali N, Hattersley AT, Havulinna AS, Hayward C, Heard Costa NL, Heath AC, Hebebrand J, Heid IM, den Heijer M, Hengstenberg C, Herzig KH, Hicks AA, Hingorani A, Hinney A, Hirschhorn JN, Hofman A, Holmes CC, Homuth G, Hottenga JJ, Hovingh KG, Hu FB, Hu YJ, Huffman JE, Hui J, Huikuri H, Humphries SE, Hung J, Hunt SE, Hunter D, Hveem K, Hyppönen E, Igl W, Illig T, Ingelsson E, Iribarren C, Isomaa B, Jackson AU, Jacobs KB, James AL, Jansson JO, Jarick I, Jarvelin MR, Jöckel KH, Johansson Å, Johnson T, Jolley J, Jørgensen T, Jousilahti P, Jula A, Justice AE, Kaakinen M, Kähönen M, Kajantie E, Kanoni S, Kao WH, Kaplan LM, Kaplan RC, Kaprio J, Kapur K, Karpe F, Kathiresan S, Kee F, Keinanen Kiukaanniemi SM, Ketkar S, Kettunen J, Khaw KT, Kiemeney LA, Kilpeläinen TO, Kinnunen L, Kivimaki M, Kivmaki M, Van der Klauw MM, Kleber ME, Knowles JW, Koenig W, Kolcic I, Kolovou G, König IR, Koskinen S, Kovacs P, Kraft P, Kraja AT, Kristiansson K, KrjutÅjkov K, Kroemer HK, Krohn JP, Krzelj V, Kuh D, Kulzer JR, Kumari M, Kutalik Z, Kuulasmaa K, Kuusisto J, Kvaloy K, Laakso M, Laitinen JH, Lakka TA, Lamina C, Langenberg C, Lantieri O, Lathrop GM, Launer LJ, Lawlor DA, Lawrence RW, Leach IM, Lecoeur C, Lee SH, Lehtimäki T, Leitzmann MF, Lettre G, Levinson DF, Li G, Li S, Liang L, Lin DY, Lind L, Lindgren CM, Lindström J, Liu J, Liuzzi A, Locke AE, Lokki ML, Loley C, Loos RJ, Lorentzon M, Luan J, Luben RN, Ludwig B, Madden PA, Mägi R, Magnusson PK, Mangino M, Manunta P, Marek D, Marre M, Martin NG, März W, Maschio A, Mathieson I, McArdle WL, McCaroll SA, McCarthy A, McCarthy MI, McKnight B, Medina Gomez C, Medland SE, Meitinger T, Metspalu A, van Meurs JB, Meyre D, Midthjell K, Mihailov E, Milani L, Min JL, Moebus S, Moffatt MF, Mohlke KL, Molony C, Monda KL, Montgomery GW, Mooser V, Morken MA, Morris AD, Morris AP, Mühleisen TW, Müller Nurasyid M, Munroe PB, Musk AW, Narisu N, Navis G, Neale BM, Nelis M, Nemesh J, Neville MJ, Ngwa JS, Nicholson G, Nieminen MS, Njølstad I, Nohr EA, Nolte IM, North KE, Nöthen MM, Nyholt DR, O'Connell JR, Ohlsson C, Oldehinkel AJ, van Ommen GJ, Ong KK, Oostra BA, Ouwehand WH, Palmer CN, Palmer LJ, Palotie A, Paré G, Parker AN, Paternoster L, Pawitan Y, Pechlivanis S, Peden JF, Pedersen NL, Pedersen O, Pellikka N, Peltonen L, Penninx B, Perola M, Perry JR, Person T, Peters A, Peters MJ, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Power C, Pramstaller PP, Preuss M, Price JF, Prokopenko I, Province MA, Psaty BM, Purcell S, Pütter C, Qi L, Quertermous T, Radhakrishnan A, Raitakari O, Randall JC, Rauramaa R, Rayner NW, Rehnberg E, Rendon A, Ridderstråle M, Ridker PM, Ripatti S, Rissanen A, Rivadeneira F, Rivolta C, Robertson NR, Rose LM, Rudan I, Saaristo TE, Sager H, Salomaa V, Samani NJ, Sambrook JG, Sanders AR, Sandholt C, Sanna S, Saramies J, Schadt EE, Scherag A, Schipf S, Schlessinger D, Schreiber S, Schunkert H, Schwarz PE, Scott LJ, Shi J, Shin SY, Shuldiner AR, Shungin D, Signorini S, Silander K, Sinisalo J, Skrobek B, Smit JH, Smith AV, Smith GD, Snieder H, Soranzo N, Sørensen TI, Sovio U, Spector TD, Speliotes EK, Stančáková A, Stark K, Stefansson K, Steinthorsdottir V, Stephens JC, Stirrups K, Stolk RP, Strachan DP, Strawbridge RJ, Stringham HM, Stumvoll M, Surakka I, Swift AJ, Syvanen AC, Tammesoo ML, Teder Laving M, Teslovich TM, Teumer A, Theodoraki EV, Thomson B, Thorand B, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tönjes A, Tregouet DA, Tremoli E, Trip MD, Tuomi T, Tuomilehto J, Tyrer J, Uda M, Uitterlinden AG, Usala G, Uusitupa M, Valle TT, Vandenput L, Vatin V, Vedantam S, de Vegt F, Vermeulen SH, Viikari J, Virtamo J, Visscher PM, Vitart V, Van Vliet Ostaptchouk JV, Voight BF, Vollenweider P, Volpato CB, Völzke H, Waeber G, Waite LL, Wallaschofski H, Walters GB, Wang Z, Wareham NJ, Watanabe RM, Watkins H, Weedon MN, Welch R, Weyant RJ, Wheeler E, White CC, Wichmann HE, Widen E, Wild SH, Willemsen G, Willer CJ, Wilsgaard T, Wilson JF, van Wingerden S, Winkelmann BR, Winkler TW, Witte DR, Witteman JC, Wolffenbuttel BH, Wong A, Wood AR, Workalemahu T, Wright AF, Yang J, Yarnell JW, Zgaga L, Zhao JH, Zillikens MC, Zitting P, Zondervan KT, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis, G, Absher, D, Alavere, H, Albrecht, E, Allen, H, Almgren, P, Amin, N, Amouyel, P, Anderson, D, Arnold, A, Arveiler, D, Aspelund, T, Asselbergs, F, Assimes, T, Atalay, M, Attwood, A, Atwood, L, Bakker, S, Balkau, B, Balmforth, A, Barlassina, C, Barroso, I, Basart, H, Bauer, S, Beckmann, J, Beilby, J, Bennett, A, Ben Shlomo, Y, Bergman, R, Bergmann, S, Berndt, S, Biffar, R, Di Blasio, A, Boehm, B, Boehnke, M, Boeing, H, Boerwinkle, E, Bolton, J, Bonnefond, A, Bonnycastle, L, Boomsma, D, Borecki, I, Bornstein, S, Bouatia Naji, N, Boucher, G, Bragg Gresham, J, Brambilla, P, Bruinenberg, M, Buchanan, T, Buechler, C, Cadby, G, Campbell, H, Caulfield, M, Cavalcanti Proença, C, Cesana, G, Chanock, S, Chasman, D, Chen, Y, Chines, P, Clegg, D, Coin, L, Collins, F, Connell, J, Cookson, W, Cooper, M, Cupples, L, Cusi, D, Day, I, Dedoussis, G, Dei, M, Deloukas, P, Dermitzakis, E, Dimas, A, Dimitriou, M, Dixon, A, Dörr, M, van Duijn, C, Ebrahim, S, Edkins, S, Eiriksdottir, G, Eisinger, K, Eklund, N, Elliott, P, Erbel, R, Erdmann, J, Erdos, M, Eriksson, J, Estrada, K, Evans, D, de Faire, U, Farrall, M, Feitosa, M, Ferrario, M, Ferrières, J, Fischer, K, Fisher, E, Fowkes, G, Fox, C, Franke, L, Franks, P, Fraser, R, Frau, F, Frayling, T, Freimer, N, Froguel, P, Fu, M, Gaget, S, Ganna, A, Gejman, P, Gentilini, D, Geus, E, Gieger, C, Gigante, B, Gjesing, A, Glazer, N, Goddard, M, Goel, A, Grallert, H, Gräßler, J, Grönberg, H, Groop, L, Groves, C, Gudnason, V, Guiducci, C, Gyllensten, U, Hall, A, Hall, P, Hallmans, G, Hamsten, A, Hansen, T, Haritunians, T, Harris, T, van der Harst, P, Hartikainen, A, Hassanali, N, Hattersley, A, Havulinna, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, den Heijer, M, Hengstenberg, C, Herzig, K, Hicks, A, Hingorani, A, Hinney, A, Hirschhorn, J, Hofman, A, Holmes, C, Homuth, G, Hottenga, J, Hovingh, K, Hu, F, Hu, Y, Huffman, J, Hui, J, Huikuri, H, Humphries, S, Hung, J, Hunt, S, Hunter, D, Hveem, K, Hyppönen, E, Igl, W, Illig, T, Ingelsson, E, Iribarren, C, Isomaa, B, Jackson, A, Jacobs, K, James, A, Jansson, J, Jarick, I, Jarvelin, M, Jöckel, K, Johansson, Å, Johnson, T, Jolley, J, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kähönen, M, Kajantie, E, Kanoni, S, Kao, W, Kaplan, L, Kaplan, R, Kaprio, J, Kapur, K, Karpe, F, Kathiresan, S, Kee, F, Keinanen Kiukaanniemi, S, Ketkar, S, Kettunen, J, Khaw, K, Kiemeney, L, Kinnunen, L, Kivimaki, M, Kivmaki, M, Van der Klauw, M, Kleber, M, Knowles, J, Koenig, W, Kolcic, I, Kolovou, G, König, I, Koskinen, S, Kovacs, P, Kraft, P, Kraja, A, Kristiansson, K, 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S, Shuldiner, A, Shungin, D, Signorini, S, Silander, K, Sinisalo, J, Skrobek, B, Smit, J, Smith, A, Smith, G, Snieder, H, Soranzo, N, Sørensen, T, Sovio, U, Spector, T, Speliotes, E, Stančáková, A, Stark, K, Stefansson, K, Steinthorsdottir, V, Stephens, J, Stirrups, K, Stolk, R, Strachan, D, Strawbridge, R, Stringham, H, Stumvoll, M, Surakka, I, Swift, A, Syvanen, A, Tammesoo, M, Teder Laving, M, Teslovich, T, Teumer, A, Theodoraki, E, Thomson, B, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Timpson, N, Tönjes, A, Tregouet, D, Tremoli, E, Trip, M, Tuomi, T, Tuomilehto, J, Tyrer, J, Uda, M, Uitterlinden, A, Usala, G, Uusitupa, M, Valle, T, Vandenput, L, Vatin, V, de Vegt, F, Vermeulen, S, Viikari, J, Virtamo, J, Visscher, P, Vitart, V, Van Vliet Ostaptchouk, J, Voight, B, Vollenweider, P, Volpato, C, Völzke, H, Waeber, G, Waite, L, Wallaschofski, H, Walters, G, Wang, Z, Wareham, N, Watanabe, R, Watkins, H, Weedon, M, Welch, R, Weyant, R, Wheeler, E, White, C, Wichmann, H, Widen, E, Wild, S, Willemsen, G, Willer, C, Wilsgaard, T, Wilson, J, van Wingerden, S, Winkelmann, B, Witte, D, Witteman, J, Wolffenbuttel, B, Wong, A, Wright, A, Yang, J, Yarnell, J, Zgaga, L, Zhao, J, Zillikens, M, Zitting, P, Zondervan, K, Psychiatry, EMGO - Mental health, Plastic, Reconstructive and Hand Surgery, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Biological Psychology, EMGO+ - Mental Health, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, Abecasis, GR., Absher, D., Alavere, H., Albrecht, E., Allen, HL., Almgren, P., Amin, N., Amouyel, P., Anderson, D., Arnold, AM., Arveiler, D., Aspelund, T., Asselbergs, FW., Assimes, TL., Atalay, M., Attwood, AP., Atwood, LD., Bakker, SJ., Balkau, B., Balmforth, AJ., Barlassina, C., Barroso£££Inês£££ I., Basart, H., Bauer, S., Beckmann, JS., Beilby, JP., Bennett, AJ., Ben-Shlomo, Y., Bergman, RN., Bergmann, S., Berndt, SI., Biffar, R., Di Blasio AM., Boehm, BO., Boehnke, M., Boeing, H., Boerwinkle, 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Subjects: Quality Control, Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, media_common.quotation_subject, quality control, GWAMAS, Control (management), Medizin, Genome-wide association study, Biology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Software, SDG 17 - Partnerships for the Goals, Meta-Analysis as Topic, Comparable size, Quality (business), 030304 developmental biology, media_common, Protocol (science), 0303 health sciences, business.industry, Software package, Data science, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Genome-Wide Association Study/methods, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], quality control, genome-wide association meta-analyses, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Item does not contain fulltext Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.
Published: 2014
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17. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. 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R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018
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18. Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

Author: James R. A. Skipworth, Sebastian Krug, Florence Bühler, Sebastian Gimpfl, Joachim Mössner, Anke Tönjes, Atsushi Masamune, Adrian Saftoiu, Roland H. Pfützer, Marcella Rietschel, Heiko Witt, Felix Stickel, Jens Werner, Peter Kovacs, Nicole Soranzo, Constantin Zimmer, Martin Ziegler, Helmut Laumen, Holger Kirsten, Marco J. Bruno, Joost P.H. Drenth, Markus M. Lerch, Markus M. Nöthen, Claus Hellerbrand, Annette Peters, Philippe Lévy, Jian-Min Chen, Monika Ridinger, Giulia Martina Cavestro, Emmanuelle Masson, Milena Di Leo, Peter Simon, Peter Bugert, Péter Hegyi, Karl Mann, Miklós Sahin-Tóth, Pier Alberto Testoni, Núria Malats, Rene H. M. te Morsche, Konstantin Strauch, Stephen P. Pereira, Josef Frank, Norbert Wodarz, Halina Cichoż-Lach, Jonas Rosendahl, Alexander Schneider, Marcus Hollenbach, Olfert Landt, Markus Löffler, Sergio Pedrazzoli, Volker Keim, Matthias Löhr, Marie Motyka, Sebastian Mueller, Ralph Burkhardt, Antoni Farré, Heidi Griesmann, Falk Kiefer, Giovanni Malerba, Claudia Ruffert, Markus Scholz, Francisco X. Real, Maren Ludwig, Eszter Hegyi, Harald Grallert, Hana Algül, Vinciane Rebours, Eva Rösmann, Frank Ulrich Weiss, Sonja Mohr, Robert Grützmann, Sevastitia Iordache, Michael Soyka, Milan Macek, Peter Lichtner, Patrick Michl, Claude Férec, Giovanni Gambaro, Michael Stumvoll, Katharina Seltsam, Thomas Müller, Grazyna Jurkowska, Ewa Małecka-Panas, Sebastian Beer, Julia Mayerle, Hans-Ulrich Schulz, Lena Werner, Publica, Rosendahl, Jona, Kirsten, Holger, Hegyi, Eszter, Kovacs, Peter, Weiss, Frank Ulrich, Laumen, Helmut, Lichtner, Peter, Ruffert, Claudia, Chen, Jian min, Masson, Emmanuelle, Beer, Sebastian, Zimmer, Constantin, Seltsam, Katharina, Algül, Hana, Bühler, Florence, Bruno, Marco J, Bugert, Peter, Burkhardt, Ralph, Cavestro, GIULIA MARTINA, Cichoz lach, Halina, Farré, Antoni, Frank, Josef, Gambaro, Giovanni, Gimpfl, Sebastian, Grallert, Harald, Griesmann, Heidi, Grützmann, Robert, Hellerbrand, Clau, Hegyi, Péter, Hollenbach, Marcu, Iordache, Sevastitia, Jurkowska, Grazyna, Keim, Volker, Kiefer, Falk, Krug, Sebastian, Landt, Olfert, Leo, Milena Di, Lerch, Markus M, Lévy, Philippe, Löffler, Marku, Löhr, Matthia, Ludwig, Maren, Macek, Milan, Malats, Nuria, Malecka panas, Ewa, Malerba, Giovanni, Mann, Karl, Mayerle, Julia, Mohr, Sonja, Te Morsche, Rene H. M, Motyka, Marie, Mueller, Sebastian, Müller, Thoma, Nöthen, Markus M, Pedrazzoli, Sergio, Pereira, Stephen P, Peters, Annette, Pfützer, Roland, Real, Francisco X, Rebours, Vinciane, Ridinger, Monika, Rietschel, Marcella, Rösmann, Eva, Saftoiu, Adrian, Schneider, Alexander, Schulz, Hans ulrich, Soranzo, Nicole, Soyka, Michael, Simon, Peter, Skipworth, Jame, Stickel, Felix, Strauch, Konstantin, Stumvoll, Michael, Testoni, PIER ALBERTO, Tönjes, Anke, Werner, Lena, Werner, Jen, Wodarz, Norbert, Ziegler, Martin, Masamune, Atsushi, Mössner, Joachim, Férec, Claude, Michl, Patrick, Joost, P. H. Drenth, Witt, Heiko, Scholz, Marku, Sahin tóth, Miklós, and Gastroenterology & Hepatology
Subjects: 0301 basic medicine, Linkage disequilibrium, medicine.medical_specialty, Settore MED/12 - GASTROENTEROLOGIA, Population, Genome Wide Association Study, Chronic Pancreatitis, Genetic Rearrangement, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Gastroenterology, chronic pancreatitis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Genetic predisposition, medicine, Allele, education, Genetics, education.field_of_study, medicine.disease, ddc, genetic rearrangement, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Genome wide association study, Pancreatitis, chronic pancreatiti, Chronic pancreatitis, Genetic rearrangement
Abstract: ObjectiveAlcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.ResultsWe replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.ConclusionAn inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
Published: 2018

19. The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer

Author: Bernhard Radlwimmer, Mario Hlevnjak, Wei Wang, Kathrin V. Schmidt, M. Kirchgäßner, A. E. Lykkesfeldt, Verena Thewes, Guido Sauter, Martje Tönjes, Stefanie Heck, Ulrich Deuschle, Magdalena Schlotter, Hans-Peter Sinn, P. Windisch, Nathaniel Melling, Jürgen G. Okun, Peter Lichter, S. Kaulfuss, Andreas Schneeweiss, Yonghe Wu, Marc Zapatka, Niclas Kneisel, Reinhard Büttner, Ronald Simon, Tobias Anzeneder, H. Hess-Stumpp, and Petra Schroeter
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, Proliferation index, Breast Neoplasms, Branched chain amino acid transaminase 1, Biology, Small hairpin RNA, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Growth factor receptor, Cell Movement, Cell Line, Tumor, Internal medicine, Genetics, medicine, Animals, Humans, skin and connective tissue diseases, Molecular Biology, Transaminases, Cell Proliferation, Mice, Inbred BALB C, Fulvestrant, Gene Expression Profiling, Estrogen Antagonists, Estrogen Receptor alpha, Cancer, medicine.disease, Antiestrogen, Up-Regulation, Tamoxifen, 030104 developmental biology, Endocrinology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, MCF-7 Cells, Cancer research, Heterografts, Female, medicine.drug
Abstract: Antiestrogen-resistant and triple-negative breast tumors pose a serious clinical challenge because of limited treatment options. We assessed global gene expression changes in antiestrogen-sensitive compared with antiestrogen-resistant (two tamoxifen resistant and two fulvestrant resistant) MCF-7 breast cancer cell lines. The branched-chain amino acid transaminase 1 (BCAT1), which catalyzes the first step in the breakdown of branched-chain amino acids, was among the most upregulated transcripts in antiestrogen-resistant cells. Elevated BCAT1 expression was confirmed in relapsed tamoxifen-resistant breast tumor specimens. High intratumoral BCAT1 levels were associated with a reduced relapse-free survival in adjuvant tamoxifen-treated patients and overall survival in unselected patients. On a tissue microarray (n=1421), BCAT1 expression was detectable in 58% of unselected primary breast carcinomas and linked to a higher Ki-67 proliferation index, as well as histological grade. Interestingly, BCAT1 was predominantly expressed in estrogen receptor-α-negative/human epidermal growth factor receptor-2-positive (ERα-negative/HER-2-positive) and triple-negative breast cancers in independent patient cohorts. The inverse relationship between BCAT1 and ERα was corroborated in various breast cancer cell lines and pharmacological long-term depletion of ERα induced BCAT1 expression in vitro. Mechanistically, BCAT1 indirectly controlled expression of the cell cycle inhibitor p27Kip1 thereby affecting pRB. Correspondingly, phenotypic analyses using a lentiviral-mediated BCAT1 short hairpin RNA knockdown revealed that BCAT1 sustains proliferation in addition to migration and invasion and that its overexpression enhanced the capacity of antiestrogen-sensitive cells to grow in the presence of antiestrogens. Importantly, silencing of BCAT1 in an orthotopic triple-negative xenograft model resulted in a massive reduction of tumor volume in vivo, supporting our findings that BCAT1 is necessary for the growth of hormone-independent breast tumors.
Published: 2017
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20. HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1 and Non-Insulin-Treated Type 2 Diabetes

Author: Christoph Engel, Nora Klöting, Michael Stumvoll, Joachim Thiery, Lucas Massier, Peter Kovacs, Katrin Horn, Thomas Jacobi, Markus Scholz, Ilias Doxiadis, Anke Tönjes, Matthias Blüher, Peter Ahnert, Alexander Schuch, Ralph Burkhardt, and Markus Löffler
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DNA Mutational Analysis, Genes, MHC Class II, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Type 2 diabetes, Human leukocyte antigen, Biology, Biochemistry, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Gene Frequency, Diabetes mellitus, Internal medicine, Germany, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Allele, Genetic Association Studies, Aged, Genetics, Type 1 diabetes, Biochemistry (medical), Haplotype, Middle Aged, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Haplotypes, Female
Abstract: Context Common genetic susceptibility may underlie the frequently observed co-occurrence of type 1 and type 2 diabetes in families. Given the role of HLA class II genes in the pathophysiology of type 1 diabetes, the aim of the present study was to test the association of high density imputed human leukocyte antigen (HLA) genotypes with type 2 diabetes. Objectives and Design Three cohorts (Ntotal = 10 413) from Leipzig, Germany were included in this study: LIFE-Adult (N = 4649), LIFE-Heart (N = 4815) and the Sorbs (N = 949) cohort. Detailed metabolic phenotyping and genome-wide single nucleotide polymorphism (SNP) data were available for all subjects. Using 1000 Genome imputation data, HLA genotypes were imputed on 4-digit level and association tests for type 2 diabetes, and related metabolic traits were conducted. Results In a meta-analysis including all 3 cohorts, the absence of HLA-DRB5 was associated with increased risk of type 2 diabetes (P = 0.001). In contrast, HLA-DQB*06:02 and HLA-DQA*01:02 had a protective effect on type 2 diabetes (P = 0.005 and 0.003, respectively). Both alleles are part of the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02, which was also associated with reduced risk of type 2 diabetes (OR 0.84; P = 0.005). On the contrary, the DRB1*07:01~DQA1*02:01~DQB1*03:03 was identified as a risk haplotype in non–insulin-treated diabetes (OR 1.37; P = 0.002). Conclusions Genetic variation in the HLA class II locus exerts risk and protective effects on non–insulin-treated type 2 diabetes. Our data suggest that the genetic architecture of type 1 diabetes and type 2 diabetes might share common components on the HLA class II locus.
Published: 2019

21. Atg7 Knockdown Reduces Chemerin Secretion in Murine Adipocytes

Author: Matthias Blüher, Peter Kovacs, Michael Stumvoll, Anke Tönjes, John T. Heiker, Henrike O. Heyne, Jacqueline Krüger, Paolo Piaggi, Claudia Gebhardt, Leslie J. Baier, Assaf Rudich, Sascha Heinitz, and Juliane Weiner
Subjects: Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Adipose tissue, Biology, Biochemistry, Autophagy-Related Protein 7, Body Mass Index, chemistry.chemical_compound, Mice, Endocrinology, Internal medicine, Adipocyte, 3T3-L1 Cells, medicine, Adipocytes, Chemerin, Animals, Humans, Luciferase, Secretion, Obesity, Clinical Research Articles, Adiposity, Aged, Gene knockdown, Biochemistry (medical), Autophagy, Middle Aged, In vitro, Diet, chemistry, Adipose Tissue, Gene Knockdown Techniques, biology.protein, Intercellular Signaling Peptides and Proteins, Female, Chemokines
Abstract: Context In individuals with obesity, adipocyte endocrine function is affected by altered autophagy. Genetic variants in autophagy-related gene 7 (ATG7) correlated with serum chemerin (RARRES2) concentrations. Objectives To investigate a functional interplay between chemerin and ATG7, how it may relate to autophagy-mediated adipocyte dysfunction in obesity, and the relevance of genetic ATG7 variants in chemerin physiology. Design Adipose ATG7 mRNA expression and adiposity measures were available in two human study cohorts. The effect of a high-calorie diet on adipose Rarres2 and Atg7 expression was investigated in mice. In 3T3-L1 adipocytes, the effect of Atg7 knockdown on chemerin expression and secretion was studied. The influence of single nucleotide polymorphisms on ATG7 transcription and chemerin physiology was investigated using a luciferase assay. Setting Mouse model, clinical trials, in vitro studies. Participants Native American (n = 83) and white (n = 100) cohorts. Main outcome measure Adipocyte chemerin expression and secretion. Results In mice fed a high-calorie diet, adipose Atg7 mRNA expression did not parallel an increase in Rarres2 mRNA expression. ATG7 mRNA expression in human subcutaneous adipose tissue correlated with body mass index, fat mass (r > 0.27; P < 0.01), and adipocyte cell size (r > 0.24; P < 0.02). Atg7 knockdown in 3T3-L1 adipocytes decreased chemerin secretion by 22% (P < 0.04). Rs2606729 in ATG7 was predicted to alter ATG7 transcription and induced higher luciferase activity in vitro (P < 0.0001). Conclusions Human adipose ATG7 mRNA expression relates to measures of adiposity. Atg7 knockdown reduces chemerin secretion from adipocytes in vitro, supportive of a functional interplay between ATG7 and chemerin in autophagy-mediated adipocyte dysfunction.
Published: 2019

22. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author: David Torrents, Thorkild I. A. Sørensen, André G. Uitterlinden, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Joachim Heinrich, Anna Murray, Nicholas J. Timpson, George Dedoussis, Beverley M. Shields, Timo A. Lakka, Lawrence J. Beilin, Carmen J. Marsit, Katharina E. Schraut, Marie Standl, Torben Hansen, James F. Wilson, Jonas Bacelis, Allan Vaag, Louis J. Muglia, Wei Ang, Josep M. Mercader, Ruifang Li-Gao, Ying Wu, Jessica Tyrrell, Pål R. Njølstad, Mohammad Hadi Zafarmand, Marie-France Hivert, Ioanna Ntalla, Debbie A Lawlor, Martina Müller-Nurasyid, Alana Cavadino, Natalia Vilor-Tejedor, Andrew R. Wood, Zoltán Kutalik, Jodie N. Painter, Tanja G. M. Vrijkotte, Kyle J. Gaulton, Xavier Estivill, George Davey Smith, Christine Power, Andrew T. Hattersley, Berthold Hocher, Gibran Hemani, Sheila J. Barton, Aino-Maija Eloranta, Kathryn L. Lunetta, Kim F. Michaelsen, Frank Geller, Bjarke Feenstra, Carol A. Wang, Peter Vollenweider, Wieland Kiess, Anubha Mahajan, Elina Hyppönen, Elisabeth M. van Leeuwen, Felix R. Day, Natalie R. van Zuydam, Leda Chatzi, Bo L. Chawes, Antje Körner, Dennis O. Mook-Kanamori, Ken K. Ong, Joanne M. Murabito, David M. Hougaard, Jian'an Luan, Letizia Marullo, Catharina E. M. van Beijsterveldt, Yik Ying Teo, Andrew P. Morris, Sarah E. Medland, Juan Fernández-Tajes, Jouke-Jan Hottenga, Frits R. Rosendaal, Inga Prokopenko, Katja Pahkala, Struan F.A. Grant, Sylvain Sebert, Judith B. Borja, Camilla Schmidt Morgen, Charlotta Pisinger, Jia Chen, Øyvind Helgeland, Christian Theil Have, Vincent W. V. Jaddoe, Marjolein N. Kooijman, Mika Kähönen, Timothy M. Frayling, Diana L. Cousminer, Bo Jacobsson, Antoine H. C. van Kampen, Eco J. C. de Geus, Manolis Kogevinas, Rico Rueedi, Grant W. Montgomery, Raimo Joro, Craig E. Pennell, Jonathan P. Bradfield, Janine F. Felix, Ge Zhang, Loreto Santa-Marina, Kalliope Panoutsopoulou, John R. B. Perry, Jeff Murray, Albert Hofman, Terho Lehtimäki, John W. Holloway, Barbera D. C. van Schaik, Pedro Marques-Vidal, Ronny Myhre, Haja N. Kadarmideen, Robert A. Scott, Frank D. Mentch, Katherine S. Ruth, Hans Bisgaard, Marjo-Riitta Järvelin, Catherine Allard, Rachel M. Freathy, Julie A. Marsh, Mariona Bustamante, Elisabeth Thiering, Cæcilie Trier, Marcus A. Tuke, William L. Lowe, Elisabeth Widen, Caroline L Relton, Christoph Reichetzeder, Penelope A. Lind, M. Geoffrey Hayes, Charles Laurin, Tarunveer S. Ahluwalia, Meike Bartels, Mads Melbye, Claudia Langenberg, Ke Hao, Shouneng Peng, Nicholas J. Wareham, Susan M. Ring, Hamdi Mbarek, Mario Murcia, Jing Hua Zhao, Michael Nodzenski, Cornelia M. van Duijn, Hakon Hakonarson, Hanieh Yaghootkar, Po-Ru Loh, Linda S. Adair, Sílvia Bonàs-Guarch, Eleftheria Zeggini, Sarah Metrustry, Shikta Das, Gonneke Willemsen, Ana Espinosa, Lavinia Paternoster, Marc Vaudel, Theresia M. Schnurr, Michael Stumvoll, David M. Evans, Bridget A. Knight, Luigi Bouchard, Robin N Beaumont, Mustafa Atalay, Zhen Qiao, Denise M. Scholtens, Klaus Bønnelykke, Samuel E. Jones, Peter K. Joshi, Oluf Pedersen, Jin-Fang Chai, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Hazel Inskip, Sara M. Willems, Cilius Esmann Fonvig, Momoko Horikoshi, Ellen A. Nohr, Jani Heikkinen, Emil V. R. Appel, Niels Grarup, Michael N. Weedon, Rebecca C Richmond, Peter Kovacs, Jorma Viikari, Amanda J. Bennett, Jens-Christian Holm, Carolina Medina-Gomez, Nicole M. Warrington, Anke Tönjes, Jakob Stokholm, Hugoline G. de Haan, Seang-Mei Saw, Ville Huikari, N. William Rayner, Johan G. Eriksson, Niina Pitkänen, Allan Linneberg, Gunn-Helen Moen, Olli T. Raitakari, Martine Vrijheid, Neil Robertson, Stefan Johansson, Tim D. Spector, Friman Sánchez, Mark I. McCarthy, Harri Niinikoski, Karen L. Mohlke, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Hypponen, E, Freathy, RM, EGG consortium, Medical and Clinical Psychology, University of Helsinki, Johan Eriksson / Principal Investigator, University of Helsinki, Institute for Molecular Medicine Finland, Warrington, Nicole M [0000-0003-4195-775X], Beaumont, Robin N [0000-0003-0750-8248], Day, Felix R [0000-0003-3789-7651], Helgeland, Øyvind [0000-0002-5612-2985], Laurin, Charles [0000-0003-2439-9004], Bacelis, Jonas [0000-0002-2450-732X], Feenstra, Bjarke [0000-0003-1478-649X], Mahajan, Anubha [0000-0001-5585-3420], Moen, Gunn-Helen [0000-0002-8768-0904], Schnurr, Theresia M [0000-0002-6573-4959], Grarup, Niels [0000-0001-5526-1070], Paternoster, Lavinia [0000-0003-2514-0889], Rueedi, Rico [0000-0002-6713-2214], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Metrustry, Sarah [0000-0003-2028-7486], Wang, Carol A [0000-0002-4301-3974], Joshi, Peter K [0000-0002-6361-5059], Pitkänen, Niina [0000-0001-7383-4987], Richmond, Rebecca C [0000-0003-0574-5071], Inskip, Hazel M [0000-0001-8897-1749], Holloway, John W [0000-0001-9998-0464], Estivill, Xavier [0000-0002-0723-2256], Hocher, Berthold [0000-0001-8143-0579], Lunetta, Kathryn L [0000-0002-9268-810X], Allard, Catherine [0000-0002-8829-4984], Muglia, Louis J [0000-0002-0301-8770], van Kampen, Antoine HC [0000-0003-1025-7232], van Schaik, Barbera DC [0000-0002-5568-8127], Langenberg, Claudia [0000-0002-5017-7344], Hemani, Gibran [0000-0003-0920-1055], Gaulton, Kyle J [0000-0003-1318-7161], Medina-Gomez, Carolina [0000-0001-7999-5538], Kutalik, Zoltán [0000-0001-8285-7523], Marques-Vidal, Pedro [0000-0002-4548-8500], Mbarek, Hamdi [0000-0002-1108-0371], Müller-Nurasyid, Martina [0000-0003-3793-5910], Appel, Emil VR [0000-0001-7704-6611], Fonvig, Cilius E [0000-0002-5031-0125], Hougaard, David M [0000-0001-5928-3517], Mercader, Josep M [0000-0001-8494-3660], Linneberg, Allan [0000-0002-0994-0184], Lind, Penelope A [0000-0002-3887-2598], Medland, Sarah E [0000-0003-1382-380X], Bartels, Meike [0000-0002-9667-7555], Stokholm, Jakob [0000-0003-4989-9769], Chawes, Bo L [0000-0001-6846-6243], Kovacs, Peter [0000-0002-0290-5423], Prokopenko, Inga [0000-0003-1624-7457], Tuke, Marcus A [0000-0003-0008-9263], Ruth, Katherine S [0000-0003-4966-9170], Jones, Samuel E [0000-0003-0153-922X], Zeggini, Eleftheria [0000-0003-4238-659X], Wilson, James F [0000-0001-5751-9178], Vrijkotte, Tanja GM [0000-0003-3641-4048], de Geus, Eco JCN [0000-0001-6022-2666], Kadarmideen, Haja N [0000-0001-6294-382X], Mohlke, Karen L [0000-0001-6721-153X], Sørensen, Thorkild IA [0000-0003-4821-430X], Bisgaard, Hans [0000-0003-4131-7592], Bønnelykke, Klaus [0000-0003-2003-1018], Melbye, Mads [0000-0001-8264-6785], Rivadeneira, Fernando [0000-0001-9435-9441], Felix, Janine F [0000-0002-9801-5774], Jaddoe, Vincent WV [0000-0003-2939-0041], Hansen, Torben [0000-0001-8748-3831], Hyppönen, Elina [0000-0003-3670-9399], Davey Smith, George [0000-0002-1407-8314], Morris, Andrew P [0000-0002-6805-6014], Hakonarson, Hakon [0000-0003-2814-7461], Grant, Struan FA [0000-0003-2025-5302], Lawlor, Debbie A [0000-0002-6793-2262], Njølstad, Pål R [0000-0003-0304-6728], Ong, Ken K [0000-0003-4689-7530], McCarthy, Mark I [0000-0002-4393-0510], Evans, David M [0000-0003-0663-4621], Freathy, Rachel M [0000-0003-4152-2238], Apollo - University of Cambridge Repository, Department of Medical and Clinical Genetics, Institute for Molecular Medicine Finland, Neuroscience Center, Doctoral Programme Brain & Mind, Ecology and Evolutionary Biology, University of Helsinki, Research Groups, Department of General Practice and Primary Health Care, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Doctoral Programme in Clinical Research, Doctoral Programme in Oral Sciences, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University Management, Epidemiology, Erasmus MC other, Internal Medicine, Pediatrics, Epidemiology and Data Science, APH - Global Health, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, ARD - Amsterdam Reproduction and Development, Experimental Immunology, Public and occupational health, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, Netherlands Twin Register (NTR), LD SCORE REGRESSION, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, DISEASE, Fetal Development, 0302 clinical medicine, Models, Pregnancy, Risk Factors, Genotype, Birth Weight, maternal genetic, 030212 general & internal medicine, Maternal-Fetal Exchange, 0303 health sciences, Body Height/genetics, 1184 Genetics, developmental biology, physiology, Heart Diseases/etiology, Single Nucleotide, ASSOCIATION, Metabolic Diseases/etiology, 3. Good health, Type 2/etiology, MENDELIAN RANDOMIZATION, GROWTH, Female, Maternal Inheritance, Maternal Inheritance/genetics, Adult, Blood Pressure/genetics, Heart Diseases, Offspring, Birth weight, cardio-metabolic health outcomes, Biology, Diabetes Mellitus, Type 2/etiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic, Metabolic Diseases, SDG 3 - Good Health and Well-being, Diabetes mellitus, Mendelian randomization, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Glycemic, Fetus, IDENTIFICATION, Models, Genetic, Infant, Newborn, Infant, birth weight, DIABETES-MELLITUS, medicine.disease, Newborn, Fetal Development/genetics, Body Height, Maternal-Fetal Exchange/genetics, LIFE, Blood pressure, Diabetes Mellitus, Type 2, ORIGINS, Institut für Ernährungswissenschaft, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.
Published: 2019
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23. Exome-derived adiponectin-associated variants implicate obesity and lipid biology

Author: Peter Kovacs, Judith B. Borja, Karen L. Mohlke, Jennifer Kriebel, Kent D. Taylor, Stuart MacGregor, Ruth J. F. Loos, Carol A. Wang, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Jaeyoung Hong, Yingchang Lu, Leslie A. Lange, Terho Lehtimäki, Matthias Blüher, Cassandra N. Spracklen, Michael A. Province, Craig E. Pennell, Laura B. L. Wittemans, Yii-Der Ida Chen, Alex P. Reiner, Nicholas J. Wareham, Massimo Mangino, Kristin L. Young, Tuomas O. Kilpeläinen, David A. Mackey, Michael Preuss, Mika Kähönen, Sara M. Willems, Paraskevi Chirstofidou, Tamara B. Harris, Matthew A. Allison, Michael Boehnke, Jian'an Luan, Cristina Venturini, Kari E. North, Chelsea K. Raulerson, Linda Broer, Paul M. Ridker, Colleen M. Sitlani, Xiuqing Guo, Leo-Pekka Lyytikäinen, Neil Roberston, Pekka Jousilahti, Barbara McKnight, M. Arfan Ikram, Heather M. Highland, Torben Hansen, Niels Grarup, Satu Männistö, James G. Wilson, Konstantin Strauch, Mariaelisa Graff, Ayse Demirkan, Rebecca S. Fine, Tugce Karaderi, Linda S. Adair, Jie Yao, Olli T. Raitakari, Zoltán Kutalik, Jeffrey Haesser, Veikko Salomaa, Sophie Molnos, Rebecca D. Jackson, Renée de Mutsert, Markku Laakso, Mark I. McCarthy, Carolina Medina-Gomez, America A. Sandoval-Zárate, Anke Tönjes, Daniel I. Chasman, Shuai Wang, Michael Stumvoll, Jette Bork-Jensen, Claudia Langenberg, Paul L. Auer, Anubha Mahajan, Claudia Schurmann, Mary F. Feitosa, Melissa E. Garcia, Tim D. Spector, Aruna D. Pradhan, Jorge R. Kizer, Timothy M. Frayling, Ying Wu, James B. Meigs, Andrew P. Morris, Harald Grallert, André G. Uitterlinden, Cecilia M. Lindgren, Traci M. Bartz, Mike A. Nalls, Erik Ingelsson, Jerome I. Rotter, Mark Walker, Ruifang Li-Gao, Ivana Nedeljkovic, Najaf Amin, Hanieh Yaghootkar, Dennis O. Mook-Kanamori, Betina H. Thuesen, Lars Lind, Jin Li, Epidemiology, Internal Medicine, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, University Management, Biostatistics Helsinki, University of Helsinki, Institute for Molecular Medicine Finland, Complex Disease Genetics, and Medical and Clinical Psychology
Subjects: Male, 0301 basic medicine, Candidate gene, Adipose tissue, Genome-wide association study, DISEASE, CANDIDATE GENES, 0302 clinical medicine, Cqardio metabolic traits, RARE, Exome, Genetics (clinical), Aged, 80 and over, Genetics, 0303 health sciences, 1184 Genetics, developmental biology, physiology, Hispanic or Latino, Middle Aged, Lipids, Phenotype, ADIPOSE-TISSUE, Adipose Tissue, 030220 oncology & carcinogenesis, Medical genetics, Female, CIRCULATING ADIPONECTIN, Adiponectin, Adult, EXPRESSION, medicine.medical_specialty, Adolescent, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, Polymorphism, Single Nucleotide, Article, White People, Young Adult, 03 medical and health sciences, Cardio Metabolic Traits, Genome-wide Association Study, Obesity, SDG 3 - Good Health and Well-being, medicine, GLYCEMIC TRAITS, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Gene, METAANALYSIS, 030304 developmental biology, Aged, PLASMA ADIPONECTIN, Correction, medicine.disease, Human genetics, Black or African American, 030104 developmental biology, Expression quantitative trait loci, 3111 Biomedicine
Abstract: Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p -7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p -4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
Published: 2019
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24. Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

Author: Wieland Kiess, Josée Dupuis, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, George Dedoussis, Frida Renström, Carolina Medina-Gomez, Tamara B. Harris, Cramer Christensen, Audrey Y. Chu, Nicola L. Beer, Emil V. R. Appel, Niels Grarup, Fredrik Karpe, Mark I. McCarthy, Yuning Chen, Veikko Salomaa, Sylvain Sebert, Richard A. Jensen, Joel N. Hirschhorn, Lars Lind, Jocelyn E. Manning Fox, Caroline Hayward, Patrick E. MacDonald, Matti Uusitupa, Stavroula Kanoni, Carola Marzi, Kenneth Rice, Leslie A. Lange, Ken Sin Lo, Jennifer L. Asimit, Nisa M. Maruthur, Leonard Lipovich, James S. Floyd, Rona J. Strawbridge, Magdalena Zoledziewska, Anne Raimondo, Robert Sladek, Alexandra I. F. Blakemore, Hugoline G. de Haan, Danish Saleheen, Ji Chen, Neil Robertson, Ching-Yu Cheng, Heiner Boeing, Min A. Jhun, Marjo-Riitta Järvelin, Anubha Mahajan, Rainer Rauramaa, Satu Männistö, Paul M. Ridker, Ivan Brandslund, Hester M. den Ruijter, Tien Yin Wong, Alison D. Murray, Jaakko Tuomilehto, Xueling Sim, Igor Rudan, Martijn van de Bunt, Jin Li, Marit E. Jørgensen, Marie-France Hivert, Archie Campbell, Salman M. Tajuddin, Pekka Jousilahti, Lawrence F. Bielak, Juan P. Fernandez, Eleanor Wheeler, Alan B. Zonderman, Anne Clark, Lori L. Bonnycastle, Kurt Lohman, Peter Kovacs, Jung-Jin Lee, Jennifer Wessel, Wesam A Alhejily, Gerard Pasterkamp, John M. Starr, Ping An, Matthias Blüher, Jian'an Luan, Hanieh Yeghootkar, Jakob Stokholm, Michael Roden, Blair H. Smith, Johanna Jakobsdottir, Franco Giulianini, Andrianos M. Yiorkas, Hidetoshi Kitajima, Michael A. Province, Aliki-Eleni Farmaki, Kerrin S. Small, Juha Saltevo, Robert A. Scott, Alena Stančáková, Gaëlle Marenne, Asif Rasheed, Ruth J. F. Loos, David J. Porteous, Cecilia M. Lindgren, Inês Barroso, Gail Davies, Anna L. Gloyn, Shuai Wang, Paul Redmond, Xiuqing Guo, Ele Ferrannini, Mariaelisa Graff, Cornelia M. van Duijn, Juha Auvinen, David R. Weir, Kay-Tee Kaw, Tarunveer S. Ahluwalia, Olov Rolandsson, Wei Zhao, Paul Elliott, Torben Hansen, Abbas Dehghan, Bram P. Prins, Michiel L. Bots, Alison Pattie, Jun Liu, Gonçalo R. Abecasis, Maria Karaleftheri, Claudia Langenberg, Jan-Håkan Jansson, Marja Vääräsmäki, James S. Pankow, Rebecca S. Fine, Jaana Lindström, Ozren Polasek, Vinicius Tragante, Soren K. Thomsen, Jana K. Rundle, Najaf Amin, Saima Afaq, Jennifer A. Smith, Anne U. Jackson, Eirini Marouli, Weihua Zhang, Tim D. Spector, Paul W. Franks, Serena Sanna, Mark J. Caulfield, Heikki A. Koistinen, Jaspal S. Kooner, Tea Skaaby, Francis S. Collins, Eva Rabing Brix Petersen, Arfan Ikram, Sander W. van der Laan, Johanna Kuusisto, Jette Bork-Jensen, Daniel I. Chasman, Michele K. Evans, Emmanouil Tsafantakis, A. I. Tarasov, Ian J. Deary, Hans Bisgaard, Dennis O. Mook-Kanamori, Helen R. Warren, Kent D. Taylor, Andrew D. Morris, Eleftheria Zeggini, Sharon L.R. Kardia, Emma Ahlqvist, Gert J. de Borst, Torben Jørgensen, Antonella Mulas, Man Li, Betina H. Thuesen, Yuan Shi, Timo A. Lakka, Jie Yao, Tapani Ebeling, Natasha H. J. Ng, Sai Chen, Leena Kinnunen, Antje Körner, Klaus Bønnelykke, Lorraine Southam, Anette P. Gjesing, Ilonca Vaartjes, Heather M. Highland, Göran Hallmans, Anke Tönjes, Markku Laakso, Lenore J. Launer, Josef Coresh, Oscar H. Franco, Yongmei Liu, Beverley Balkau, Leena Moilanen, Karl-Heinz Herzig, James G. Wilson, Jennifer A. Brody, Renée de Mutsert, Alisa K. Manning, Anne E. Justice, Matthias B. Schulze, Sandosh Padmanabhan, Jose C. Florez, Shuang Feng, Heather M. Stringham, Bruce M. Psaty, Erwin P. Bottinger, Hannu Puolijoki, Vilmundur Gudnason, Leif Groop, Nicholas J. Wareham, Karina Meidtner, Andrew P. Morris, Taulant Muka, Benoit Hastoy, Panos Deloukas, Pirjo Komulainen, Ayse Demirkan, Francesco Cucca, Stefan Gustafsson, Eric Boerwinkle, Patrik Rorsman, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Allan Linneberg, Tiinamaija Tuomi, Dan E. Arking, Steve Franks, Jonathan Marten, Mark Walker, Ruifang Li-Gao, Kai Savonen, Michael Stumvoll, Andreas Fritsche, E-Shyong Tai, Mark O. Goodarzi, Matt J. Neville, Oluf Pedersen, Eero Kajantie, Ching-Ti Liu, Michael Boehnke, Aaron Leong, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, John C. Chambers, John Danesh, Sirkka Keinänen-Kiukaanniemi, Giorgio Pistis, Karen L. Mohlke, Folkert W. Asselbergs, James B. Meigs, Tibor V. Varga, Erica L. Kleinbrink, Andrew T. Hattersley, Nathan A. Bihlmeyer, Harald Grallert, Albert V. Smith, Konstantin Strauch, Jerome I. Rotter, and Frits R. Rosendaal
Subjects: medicine.medical_specialty, G6PC2, pathways, Adipose tissue, Type 2 diabetes, Biology, effector transcript, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, Internal medicine, 0502 economics and business, medicine, Glucose homeostasis, genetics, 050207 economics, 030304 developmental biology, Glycemic, 0303 health sciences, 050208 finance, Pancreatic islets, 05 social sciences, tissue, Genomics, medicine.disease, Endocrinology, medicine.anatomical_structure, chemistry, glycemic traits, Glycated hemoglobin, type 2 diabetes, 030217 neurology & neurosurgery
Abstract: SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia
Published: 2019
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25. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author: Tobias Hermle, Holger Kirsten, Karsten B. Sieber, Aiko P. J. de Vries, Su Chi Lim, Peter Kovacs, Charumathi Sabanayagam, Carl D. Langefeld, Bernhard K. Krämer, Kent D. Taylor, Janine F. Felix, Belen Ponte, Markus Loeffler, Mary F. Feitosa, Kai-Uwe Eckardt, Jianjun Liu, Katalin Dittrich, Charlene A. Wong, Uwe Völker, Adriana M. Hung, Thomas Meitinger, Anubha Mahajan, Anselm Hoppmann, Erik Ingelsson, Martin H. de Borst, Oscar H. Franco, Niek Verweij, Kai-Uwe Saum, Vilmundur Gudnason, Bram P. Prins, Carsten A. Böger, Terho Lehtimäki, Andrew A. Hicks, Todd L. Edwards, Olivier Devuyst, Peter P. Pramstaller, Katrin Horn, Leslie A. Lange, Johanne Tremblay, Jin-Fang Chai, Sahar Ghasemi, Kjell Nikus, Tanja Poulain, Massimiliano Cocca, Anna Köttgen, Eric Boerwinkle, Barry I. Freedman, Miao-Ling Chee, Man Li, Stephan J. L. Bakker, Tamara B. Harris, Albert V. Smith, Ton J. Rabelink, Dennis O. Mook-Kanamori, Iris M. Heid, Jasmin Divers, Chaolong Wang, Kathleen A. Ryan, Pavel Hamet, Silke Szymczak, Shih-Jen Hwang, Hauke Thomsen, Rainer Rettig, Ayush Giri, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Cristian Pattaro, Andrej Teren, Valencia Hui Xian Foo, Myriam Rheinberger, Audrey Y. Chu, Barbara McMullen, Franziska Grundner-Culemann, Masayuki Yasuda, Murielle Bochud, Martin Gögele, Anke Tönjes, Jeannette Lee, Adrienne Tin, Kevin Ho, Konstantin Strauch, Josef Coresh, Renée de Mutsert, Sandra Freitag-Wolf, Gardar Sveinbjornsson, Yizhe Xu, Katalin Susztak, Tien Yin Wong, Mary L. Biggs, Isleifur Olafsson, Qiong Yang, Antje Körner, Chengxiang Qiu, E-Shyong Tai, Martina Müller-Nurasyid, Ben Schöttker, Jeffrey O' Connell, Mengmeng Chen, Daniel F. Gudbjartsson, Dermot F. Reilly, Vincent W. V. Jaddoe, Damia Noce, Pim van der Harst, Sanaz Sedaghat, Chiea Chuen Khor, Adam S. Butterworth, Mathias Gorski, Robert J. Carroll, James G. Wilson, Johan Ärnlöv, Christa Meisinger, Kenneth Rice, Bettina Jung, Christian M. Shaffer, Unnur Thorsteinsdottir, Matthias Nauck, Shreeram Akilesh, Mika Kähönen, Johanna Jakobsdottir, Melanie Waldenberger, Ralph Burkhardt, Daniela Baptista, John Danesh, Benjamin B. Sun, Karlhans Endlich, Holly Kramer, Frauke Degenhardt, Wolfgang Lieb, Kari Stefansson, Joachim Thiery, Lars Lind, Nicholette D. Palmer, Sarah A. Pendergrass, Suzanne Vogelezang, Peter J. van der Most, Afshin Parsa, Markus Scholz, Florian Kronenberg, Joseph C. Maranville, Laura M. Raffield, Hermann Brenner, Wieland Kiess, Anna I. Podgornaia, Yuan Shi, Tanguy Corre, Miao-Li Chee, Deborah Mascalzoni, Bamidele O. Tayo, Navya Shilpa Josyula, Ching-Yu Cheng, Lea Gerstner, Nisha Bansal, Jerome I. Rotter, Alexander Teumer, Vilmantas Giedraitis, Raymond Noordam, Ron T. Gansevoort, Lihua Wang, Andrew P. Morris, Bruce M. Psaty, Boting Ning, Zhi Yu, Christian Fuchsberger, Matthias Wuttke, Heiko Runz, Annette Peters, Yih Chung Tham, James P. Cook, Yong Li, Chris H. L. Thio, Hilma Holm, Alessandro De Grandi, Jonathan Marten, André G. Uitterlinden, Andre Franke, Nicholas Y. Q. Tan, Otis D. Wilson, Georg Ehret, Cecilia M. Lindgren, Josyf C. Mychaleckyj, Wolfgang Koenig, Harold Snieder, Michael Stumvoll, Kozeta Miliku, M. Arfan Ikram, Teresa Nutile, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands, University of Iceland, Teumer, Alexander [0000-0002-8309-094X], Li, Yong [0000-0003-2651-8791], Wuttke, Matthias [0000-0003-3420-5082], Giri, Ayush [0000-0002-7786-4670], Qiu, Chengxiang [0000-0002-6346-8669], Kirsten, Holger [0000-0002-3126-7950], Tin, Adrienne [0000-0002-4207-5866], Feitosa, Mary F. [0000-0002-0933-2410], Chai, Jin-Fang [0000-0003-3770-1137], Cocca, Massimiliano [0000-0002-1127-7596], Gorski, Mathias [0000-0002-9103-5860], Horn, Katrin [0000-0002-5307-6936], Li, Man [0000-0002-3839-0281], Marten, Jonathan [0000-0001-6916-2014], van der Most, Peter J. [0000-0001-8450-3518], Burkhardt, Ralph [0000-0003-1924-1202], Coresh, Josef [0000-0002-4598-0669], de Borst, Martin H. [0000-0002-4127-8733], Ehret, Georg [0000-0002-5730-0675], Endlich, Karlhans [0000-0001-6052-6061], Felix, Janine F. [0000-0002-9801-5774], Franke, Andre [0000-0003-1530-5811], Freedman, Barry I. [0000-0003-0275-5530], Freitag-Wolf, Sandra [0000-0002-1069-7740], Giedraitis, Vilmantas [0000-0003-3423-2021], Grundner-Culemann, Franziska [0000-0001-9649-281X], Gudnason, Vilmundur [0000-0001-5696-0084], Hicks, Andrew A. [0000-0001-6320-0411], Ikram, M. Arfan [0000-0003-0372-8585], Ingelsson, Erik [0000-0003-2256-6972], Jaddoe, Vincent W. V. [0000-0003-2939-0041], Josyula, Navya Shilpa [0000-0003-2782-8812], Khor, Chiea-Chuen [0000-0002-1128-4729], Koenig, Wolfgang [0000-0002-2064-9603], Kovacs, Peter [0000-0002-0290-5423], Kronenberg, Florian [0000-0003-2229-1120], Lindgren, Cecilia M. [0000-0002-4903-9374], Liu, Jianjun [0000-0002-3255-3019], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Mahajan, Anubha [0000-0001-5585-3420], Mascalzoni, Deborah [0000-0003-4156-1464], Miliku, Kozeta [0000-0002-9614-7191], Müller-Nurasyid, Martina [0000-0003-3793-5910], Mychaleckyj, Josyf C. [0000-0003-2595-0005], Palmer, Nicholette D. [0000-0001-8883-2511], Poulain, Tanja [0000-0003-3825-5829], Raffield, Laura M. [0000-0002-7892-193X], Rice, Kenneth M. [0000-0002-3071-7278], Rivadeneira, Fernando [0000-0001-9435-9441], Sabanayagam, Charumathi [0000-0002-4042-4719], Smith, Albert V. [0000-0003-1942-5845], Sun, Benjamin B. [0000-0001-6347-2281], Szymczak, Silke [0000-0002-8897-9035], Taylor, Kent D. [0000-0002-2756-4370], Thio, Chris H. L. [0000-0003-2623-7172], Uitterlinden, André G. [0000-0002-7276-3387], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Völker, Uwe [0000-0002-5689-3448], Wang, Chaolong [0000-0003-3945-1012], Yang, Qiong [0000-0002-3658-1375], Devuyst, Olivier [0000-0003-3744-4767], Edwards, Todd L. [0000-0003-4318-6119], Ho, Kevin [0000-0002-3054-8697], Morris, Andrew P. [0000-0002-6805-6014], Pendergrass, Sarah A. [0000-0002-0565-6522], Rotter, Jerome I. [0000-0001-7191-1723], Stefansson, Kari [0000-0003-1676-864X], Susztak, Katalin [0000-0002-1005-3726], Scholz, Markus [0000-0002-4059-1779], Butterworth, Adam S. [0000-0002-6915-9015], Hung, Adriana M. [0000-0002-3203-1608], Pattaro, Cristian [0000-0002-4119-0109], Köttgen, Anna [0000-0002-4671-3714], Apollo - University of Cambridge Repository, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Feitosa, Mary F [0000-0002-0933-2410], van der Most, Peter J [0000-0001-8450-3518], de Borst, Martin H [0000-0002-4127-8733], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Hicks, Andrew A [0000-0001-6320-0411], Ikram, M Arfan [0000-0003-0372-8585], Jaddoe, Vincent WV [0000-0003-2939-0041], Lindgren, Cecilia M [0000-0002-4903-9374], Mychaleckyj, Josyf C [0000-0003-2595-0005], Palmer, Nicholette D [0000-0001-8883-2511], Raffield, Laura M [0000-0002-7892-193X], Rice, Kenneth M [0000-0002-3071-7278], Smith, Albert V [0000-0003-1942-5845], Sun, Benjamin B [0000-0001-6347-2281], Taylor, Kent D [0000-0002-2756-4370], Thio, Chris HL [0000-0003-2623-7172], Uitterlinden, André G [0000-0002-7276-3387], Edwards, Todd L [0000-0003-4318-6119], Morris, Andrew P [0000-0002-6805-6014], Pendergrass, Sarah A [0000-0002-0565-6522], Rotter, Jerome I [0000-0001-7191-1723], Butterworth, Adam S [0000-0002-6915-9015], and Hung, Adriana M [0000-0002-3203-1608]
Subjects: 0301 basic medicine, Drosophila melanogaster/genetics, Diabetes Mellitus/genetics, LD SCORE REGRESSION, 030232 urology & nephrology, 45/43, General Physics and Astronomy, Genome-wide association study, BLOOD-PRESSURE, Bioinformatics, GLOMERULAR-FILTRATION-RATE, Genome-wide association studies, Diabetes mellitus genetics, 0302 clinical medicine, Creatinine/urine, Risk Factors, Genome-wide, Phenomics, lcsh:Science, ddc:616, Regulation of gene expression, RISK, Gene knockdown, Kidney diseases, Multidisciplinary, HERITABILITY, Albuminuria/genetics, article, Chromosome Mapping, Kidney disease, ddc, 3. Good health, Drosophila melanogaster, Creatinine, Nýrnasjúkdómar, 692/4022/1585, Slit diaphragm, Medical genetics, medicine.symptom, Erfðarannsóknir, Medical Genetics, medicine.medical_specialty, Science, 631/208/205/2138, 610 Medicine & health, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Meta-Analysis as Topic, 360 Social problems & social services, Diabetes Mellitus, medicine, Animals, Humans, Albuminuria, Genetic Predisposition to Disease, ddc:610, EXCRETION RATE, CARDIOVASCULAR EVENTS, Genetic association, Medicinsk genetik, TRANS-EQTLS, KIDNEY-DISEASE, General Chemistry, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, COLLABORATIVE METAANALYSIS, lcsh:Q, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein)., Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria., Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.
Published: 2019
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26. Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood

Author: Qi, Ting, Wu, Yang, Zeng, Jian, Zhang, Futao, Xue, Angli, Jiang, Longda, Zhu, Zhihong, Kemper, Kathryn, Yengo, Loic, Zheng, Zhili, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand, Awadalla, Philip, Battle, Alexis, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret, Christiansen, Mark, Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina, Gibson, Gregory, Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johannes, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg-Guzman, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Markus, Marigorta, Urko M., Metspalu, Andres, Milani, Lili, Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel, Penninx, Brenda, Perola, Markus, Pervjakova, Natalia, Pierce, Brandon, Powell, Joseph, Prokisch, Holger, Psaty, Bruce, Raitakari, Olli, Ring, Susan, Ripatti, Samuli, Rotzschke, Olaf, Ruëger, Sina, Saha, Ashis, Scholz, Markus, Schramm, Katharina, Seppälä, Ilkka, Stumvoll, Michael, Sullivan, Patrick, Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, Van Dongen, Jenny, Van Meurs, Joyce, Verlouw, Joost, Völker, Uwe, Võsa, Urmo, Yaghootkar, Hanieh, Zeng, Biao, Marioni, Riccardo E., Montgomery, Grant W., Deary, Ian J., Wray, Naomi R., Visscher, Peter M., McRae, Allan F., Yang, Jian, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Integrative Neurophysiology, APH - Personalized Medicine, Psychiatry, APH - Digital Health, Internal Medicine, Institute for Molecular Medicine Finland, University Management, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Doctoral Programme in Population Health, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, and Complex Disease Genetics
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), General Physics and Astronomy, Genome-wide association study, data set, Transcriptome, 0302 clinical medicine, quantitative trait locus, expression quantitative trait locus, genetics, Tissue Distribution, lcsh:Science, Promoter Regions, Genetic, Regulation of gene expression, Genetics, 0303 health sciences, Multidisciplinary, DNA methylation, quantitative analysis, Brain, Phenotype, sample size, Enhancer Elements, Genetic, CpG site, genetic marker, enhancer region, Genetic Markers, Science, Quantitative Trait Loci, Quantitative trait locus, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, promoter region, blood, genetics of the nervous system, MD Multidisciplinary, Humans, human, gene, Gene, 030304 developmental biology, dNaM, General Chemistry, DNA, DNA Methylation, major clinical study, 030104 developmental biology, Gene Expression Regulation, Genetic marker, Expression quantitative trait loci, genome-wide association studies, gene expression, RNA, lcsh:Q, methylation, 3111 Biomedicine, gene regulation, metabolism, 030217 neurology & neurosurgery, meta analysis, Genome-Wide Association Study
Abstract: Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (rb). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hat r_b = 0.70$$\end{document}r^b=0.70 for cis-eQTLs and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hat r_ b = 0.78$$\end{document}r^b=0.78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes., To comprehend the genetic regulatory mechanisms underlying brain-related traits in humans, Qi et al. estimate the correlation of expression and DNA methylation QTL effects in cis between blood and brain and show that using blood eQTL/mQTL data of large sample size can increase power in gene discovery for brain-related traits and diseases.
Published: 2018
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27. Bone morphogenetic protein 2 (BMP2) may contribute to partition of energy storage into visceral and subcutaneous fat depots

Author: Dorit Schleinitz, Kathrin Landgraf, Peter Kovacs, Nora Klöting, Esther Guiu-Jurado, Karen Ruschke, Michael Stumvoll, Anke Tönjes, Matthias Kern, Matthias Blüher, Mark Unthan, Antje Körner, Arne Dietrich, Nina Böhler, and Mathias Faßhauer
Subjects: 0301 basic medicine, medicine.medical_specialty, animal structures, Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, fungi, Medicine (miscellaneous), Adipose tissue, Single-nucleotide polymorphism, Type 2 diabetes, Biology, Bone morphogenetic protein, medicine.disease, Obesity, Bone morphogenetic protein 2, biological factors, 03 medical and health sciences, 030104 developmental biology, Endocrinology, Adipogenesis, Internal medicine, embryonic structures, medicine, Body mass index
Abstract: Objective Bone morphogenetic proteins (BMPs) are important regulators of adipogenesis and may play a role in obesity. In this study, the hypothesis that BMP2 is related to adipose tissue (AT) distribution in obesity was tested. Methods BMP2 serum concentration (n = 439) and BMP2 and Schnurri-1 and −2 mRNA expression were measured in paired samples of visceral and subcutaneous AT from 547 individuals with a wide range of body mass index. In addition, a single nucleotide polymorphism rs979012 in the BMP2 gene was genotyped for subsequent association studies on quantitative traits related to obesity in 631 individuals. Results BMP2 and Schnurri-1 mRNA were significantly higher in visceral compared with subcutaneous AT. Compared with individuals who were healthy and lean, BMP2 expression in both depots was significantly higher in people with obesity. Significantly higher BMP2 serum concentrations were found in patients with type 2 diabetes with moderate but not morbid obesity. Schnurri-1 and −2 mRNA expression was not related to either BMP2 expression or circulating BMP2. Finally, rs979012 showed nominal association with body mass index and total cholesterol levels. Conclusions Data suggest that with increasing demand to store excessive energy, AT BMP2 expression increases and may contribute to partitioning of energy storage into visceral and subcutaneous AT depots.
Published: 2016
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28. Defining the role of common variation in the genomic and biological architecture of adult human height

Author: Wood, Ar, Esko, T, Yang, J, Vedantam, S, Pers, Th, Gustafsson, S, Chu, Ay, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, Ml, Croteau Chonka DC, Day, Fr, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, Au, Karjalainen, J, Lo, Ks, Locke, Ae, Mägi, R, Mihailov, E, Porcu, E, Randall, Jc, Scherag, A, Vinkhuyzen, Aa, Westra, Hj, Winkler, Tw, Workalemahu, T, Zhao, Jh, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, Gb, Feenstra, B, Feitosa, Mf, Fischer, K, Fraser, Rm, Goel, A, Gong, J, Justice, Ae, Kanoni, S, Kleber, Me, Kristiansson, K, Lim, U, Lotay, V, Lui, Jc, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, Ma, Nyholt, Dr, Palmer, Cd, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, Js, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, Rj, Sung, Yj, Tanaka, T, Teumer, A, Trompet, S, van der Laan SW, van Setten, J, Van Vliet Ostaptchouk JV, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Arnlöv, J, Arscott, Gm, Bandinelli, S, Barrett, A, Bellis, C, Bennett, Aj, Berne, C, Blüher, M, Bolton, Jl, Böttcher, Y, Boyd, Ha, Bruinenberg, M, Buckley, Bm, Buyske, S, Caspersen, Ih, Chines, Ps, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, Ew, De Jong PA, Deelen, J, Delgado, G, Denny, Jc, Dhonukshe Rutten, R, Dimitriou, M, Doney, As, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, Me, Geller, F, Giedraitis, V, Go, As, Grallert, H, Grammer, Tb, Gräßler, J, Grönberg, H, de Groot LC, Groves, Cj, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hannemann, A, Hartman, Ca, Hassinen, M, Hayward, C, Heard Costa NL, Helmer, Q, Hemani, G, Henders, Ak, Hillege, Hl, Hlatky, Ma, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat JJ, Illig, T, Isaacs, A, James, Al, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, An, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, Pk, Mahajan, A, Maillard, M, Mcardle, Wl, Mckenzie, Ca, Mclachlan, S, Mclaren, Pj, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, Kl, Morken, Ma, Müller, G, Müller Nurasyid, M, Musk, Aw, Narisu, N, Nauck, M, Nolte, Im, Nöthen, Mm, Oozageer, L, Pilz, S, Rayner, Nw, Renstrom, F, Robertson, Nr, Rose, Lm, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, Fr, Schunkert, H, Scott, Ra, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, Jh, Smith, Av, Smolonska, J, Stanton, Av, Stirrups, K, Stott, Dj, Stringham, Hm, Sundström, J, Swertz, Ma, Syvänen, Ac, Tayo, Bo, Thorleifsson, G, Tyrer, Jp, van Dijk, S, van Schoor NM, van der Velde, N, van Heemst, D, van Oort FV, Vermeulen, Sh, Verweij, N, Vonk, Jm, Waite, Ll, Waldenberger, M, Wennauer, R, Wilkens, Lr, Willenborg, C, Wilsgaard, T, Wojczynski, Mk, Wong, A, Wright, Af, Zhang, Q, Arveiler, D, Bakker, Sj, Beilby, J, Bergman, Rn, Bergmann, S, Biffar, R, Blangero, J, Boomsma, Di, Bornstein, Sr, Bovet, P, Brambilla, P, Brown, Mj, Campbell, H, Caulfield, Mj, Chakravarti, A, Collins, R, Collins, Fs, Crawford, Dc, Cupples, La, Danesh, J, de Faire, U, den Ruijter HM, Erbel, R, Erdmann, J, Eriksson, Jg, Farrall, M, Ferrannini, Eleuterio, Ferrières, J, Ford, I, Forouhi, Ng, Forrester, T, Gansevoort, Rt, Gejman, Pv, Gieger, C, Golay, A, Gottesman, O, Gudnason, V, Gyllensten, U, Haas, Dw, Hall, As, Harris, Tb, Hattersley, At, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hindorff, La, Hingorani, Ad, Hofman, A, Hovingh, Gk, Humphries, Se, Hunt, Sc, Hypponen, E, Jacobs, Kb, Jarvelin, Mr, Jousilahti, P, Jula, Am, Kaprio, J, Kastelein, Jj, Kayser, M, Kee, F, Keinanen Kiukaanniemi SM, Kiemeney, La, Kooner, Js, Kooperberg, C, Koskinen, S, Kovacs, P, Kraja, At, Kumari, M, Kuusisto, J, Lakka, Ta, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lupoli, S, Madden, Pa, Männistö, S, Manunta, P, Marette, A, Matise, Tc, Mcknight, B, Meitinger, T, Moll, Fl, Montgomery, Gw, Morris, Ad, Morris, Ap, Murray, Jc, Nelis, M, Ohlsson, C, Oldehinkel, Aj, Ong, Kk, Ouwehand, Wh, Pasterkamp, G, Peters, A, Pramstaller, Pp, Price, Jf, Qi, L, Raitakari, Ot, Rankinen, T, Rao, Dc, Rice, Tk, Ritchie, M, Rudan, I, Salomaa, V, Samani, Nj, Saramies, J, Sarzynski, Ma, Schwarz, Pe, Sebert, S, Sever, P, Shuldiner, Ar, Sinisalo, J, Steinthorsdottir, V, Stolk, Rp, Tardif, Jc, Tönjes, A, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, Mc, Electronic Medical Records, Genomics, Consortium, Migen, Consortium, Pagege, Consortium, LifeLines Cohort Study, Amouyel, P, Asselbergs, Fw, Assimes, Tl, Bochud, M, Boehm, Bo, Boerwinkle, E, Bottinger, Ep, Bouchard, C, Cauchi, S, Chambers, Jc, Chanock, Sj, Cooper, Rs, de Bakker PI, Dedoussis, G, Ferrucci, L, Franks, Pw, Froguel, P, Groop, Lc, Haiman, Ca, Hamsten, A, Hayes, Mg, Hui, J, Hunter, Dj, Hveem, K, Jukema, Jw, Kaplan, Rc, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, Martin, Ng, März, W, Melbye, M, Moebus, S, Munroe, Pb, Njølstad, I, Oostra, Ba, Palmer, Cn, Pedersen, Nl, Perola, M, Pérusse, L, Peters, U, Powell, Je, Power, C, Quertermous, T, Rauramaa, R, Reinmaa, E, Ridker, Pm, Rivadeneira, F, Rotter, Ji, Saaristo, Te, Saleheen, D, Schlessinger, D, Slagboom, Pe, Snieder, H, Spector, Td, Strauch, K, Stumvoll, M, Tuomilehto, J, Uusitupa, M, van der Harst, P, Völzke, H, Walker, M, Wareham, Nj, Watkins, H, Wichmann, He, Wilson, Jf, Zanen, P, Deloukas, P, Heid, Im, Lindgren, Cm, Mohlke, Kl, Speliotes, Ek, Thorsteinsdottir, U, Barroso, I, Fox, Cs, North, Ke, Strachan, Dp, Beckmann, Js, Berndt, Si, Boehnke, M, Borecki, Ib, Mccarthy, Mi, Metspalu, A, Stefansson, K, Uitterlinden, Ag, van Duijn CM, Franke, L, Willer, Cj, Price, Al, Lettre, G, Loos, Rj, Weedon, Mn, Ingelsson, E, O'Connell, Jr, Abecasis, Gr, Chasman, Di, Goddard, Me, Visscher, Pm, Hirschhorn, Jn, Frayling, T. M., Isotope Research, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Ehret, Georg Benedikt, Wood, A, Esko, T, Yang, J, Vedantam, S, Pers, T, Gustafsson, S, Chu, A, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, M, Croteau Chonka, D, Day, F, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, A, Karjalainen, J, Lo, K, Locke, A, Mägi, R, Mihailov, E, Porcu, E, Randall, J, Scherag, A, Vinkhuyzen, A, Westra, H, Winkler, T, 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Schoor N.M., Van Der Velde N., Van Heemst D., Van Oort F.V.A., Vermeulen S.H., Verweij N., Vonk J.M., Waite L.L., Waldenberger M., Wennauer R., Wilkens L.R., Willenborg C., Wilsgaard T., Wojczynski M.K., Wong A., Wright A.F., Zhang Q., Arveiler D., Bakker S.J.L., Beilby J., Bergman R.N., Bergmann S., Biffar R., Blangero J., Boomsma D.I., Bornstein S.R., Bovet P., Brambilla P., Brown M.J., Campbell H., Caulfield M.J., Chakravarti A., Collins R., Collins F.S., Crawford D.C., Cupples L.A., Danesh J., De Faire U., Den Ruijter H.M., Erbel R., Erdmann J., Eriksson J.G., Farrall M., Ferrannini E., Ferrieres J., Ford I., Forouhi N.G., Forrester T., Gansevoort R.T., Gejman P.V., Gieger C., Golay A., Gottesman O., Gudnason V., Gyllensten U., Haas D.W., Hall A.S., Harris T.B., Hattersley A.T., Heath A.C., Hengstenberg C., Hicks A.A., Hindorff L.A., Hingorani A.D., Hofman A., Hovingh G.K., Humphries S.E., Hunt S.C., Hypponen E., Jacobs K.B., Jarvelin M.-R., Jousilahti P., Jula A.M., Kaprio J., Kastelein J.J.P., Kayser M., Kee F., Keinanen-Kiukaanniemi S.M., Kiemeney L.A., Kooner J.S., Kooperberg C., Koskinen S., Kovacs P., Kraja A.T., Kumari M., Kuusisto J., Lakka T.A., Langenberg C., Le Marchand L., Lehtimaki T., Lupoli S., Madden P.A.F., Mannisto S., Manunta P., Marette A., Matise T.C., McKnight B., Meitinger T., Moll F.L., Montgomery G.W., Morris A.D., Morris A.P., Murray J.C., Nelis M., Ohlsson C., Oldehinkel A.J., Ong K.K., Ouwehand W.H., Pasterkamp G., Peters A., Pramstaller P.P., Price J.F., Qi L., Raitakari O.T., Rankinen T., Rao D.C., Rice T.K., Ritchie M., Rudan I., Salomaa V., Samani N.J., Saramies J., Sarzynski M.A., Schwarz P.E.H., Sebert S., Sever P., Shuldiner A.R., Sinisalo J., Steinthorsdottir V., Stolk R.P., Tardif J.-C., Tonjes A., Tremblay A., Tremoli E., Virtamo J., Vohl M.-C., Amouyel P., Asselbergs F.W., Assimes T.L., Bochud M., Boehm B.O., Boerwinkle E., Bottinger E.P., Bouchard C., Cauchi S., Chambers J.C., Chanock S.J., Cooper R.S., De Bakker P.I.W., Dedoussis G., Ferrucci L., Franks P.W., Froguel P., Groop L.C., Haiman C.A., Hamsten A., Hayes M.G., Hui J., Hunter D.J., Hveem K., Jukema J.W., Kaplan R.C., Kivimaki M., Kuh D., Laakso M., Liu Y., Martin N.G., Marz W., Melbye M., Moebus S., Munroe P.B., Njolstad I., Oostra B.A., Palmer C.N.A., Pedersen N.L., Perola M., Perusse L., Peters U., Powell J.E., Power C., Quertermous T., Rauramaa R., Reinmaa E., Ridker P.M., Rivadeneira F., Rotter J.I., Saaristo T.E., Saleheen D., Schlessinger D., Slagboom P.E., Snieder H., Spector T.D., Strauch K., Stumvoll M., Tuomilehto J., Uusitupa M., Van Der Harst P., Volzke H., Walker M., Wareham N.J., Watkins H., Wichmann H.-E., Wilson J.F., Zanen P., Deloukas P., Heid I.M., Lindgren C.M., Mohlke K.L., Speliotes E.K., Thorsteinsdottir U., Barroso I., Fox C.S., North K.E., Strachan D.P., Beckmann J.S., Berndt S.I., Boehnke M., Borecki I.B., McCarthy M.I., Metspalu A., Stefansson K., Uitterlinden A.G., Van Duijn C.M., Franke L., Willer C.J., Price A.L., Lettre G., Loos R.J.F., Weedon M.N., Ingelsson E., O'Connell J.R., Abecasis G.R., Chasman D.I., Goddard M.E., Visscher P.M., Hirschhorn J.N., and Frayling T.M.
Subjects: Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Electronic Medical Records and Genomics (eMEMERGEGE) Consortium, Medizin, Genome-wide association study, Adult, Analysis of Variance, Body Height/genetics, European Continental Ancestry Group/genetics, Genetic Variation/genetics, Genetics, Population, Genome-Wide Association Study/methods, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide/genetics, heritability, 0302 clinical medicine, Genome-wide, SNPS, snps, Genetics & Heredity, ddc:616, Genetics, Medical And Health Sciences, 0303 health sciences, education.field_of_study, variants, GENETIC-VARIATION, Biological Sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], body height, genetic-variation, Life Sciences & Biomedicine, Single Nucleotide/genetics, Human, European Continental Ancestry Group, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, NO, complex traits, 03 medical and health sciences, Genetic variation, heritability, adult, height, Polymorphism, Human height, PAGEGE Consortium, education, Gene, VLAG, 030304 developmental biology, Global Nutrition, Wereldvoeding, genome-wide association study, Science & Technology, Whites, Oligonucleotide Array Sequence Analysi, MUTATIONS, COMPLEX TRAITS, ta1184, Klinisk medicin, population genetics, Genetic Variation, Heritability, ta3121, mutations, Genetic architecture, Body Height, genetic variation, MIGen Consortium, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Clinical Medicine, 030217 neurology & neurosurgery, height, LifeLines Cohort Study, Developmental Biology, Genome-Wide Association Study
Abstract: Item does not contain fulltext Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Published: 2014
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29. First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes-Chapter 5: recipient monitoring and response plan for preventing disease trans

Author: Ralf R. Tönjes, Jay A. Fishman, Y Takeuchi, Linda Scobie, and Joachim Denner
Subjects: 0301 basic medicine, Swine, Xenotransplantation, medicine.medical_treatment, Transplant recipient, Transplantation, Heterologous, Immunology, Islets of Langerhans Transplantation, Endogenous retrovirus, 030230 surgery, Biology, 03 medical and health sciences, 0302 clinical medicine, Disease Transmission, Infectious, medicine, Animals, Humans, CRISPR, Transplantation, Porcine islets, Endogenous Retroviruses, Clinical trial, Diabetes Mellitus, Type 1, 030104 developmental biology, Infectious disease (medical specialty), Disease transmission
Abstract: Xenotransplantation of porcine cells, tissues, and organs may be associated with the transmission of porcine microorganisms to the human recipient. A previous, 2009, version of this consensus statement focused on strategies to prevent transmission of porcine endogenous retroviruses (PERVs). This version addresses potential transmission of all porcine microorganisms including monitoring of the recipient and provides suggested approaches to the monitoring and prevention of disease transmission. Prior analyses assumed that most microorganisms other than the endogenous retroviruses could be eliminated from donor animals under appropriate conditions which have been called "designated pathogen-free" (DPF) source animal production. PERVs integrated as proviruses in the genome of all pigs cannot be eliminated in that manner and represent a unique risk. Certain microorganisms are by nature difficult to eliminate even under DPF conditions; any such clinically relevant microorganisms should be included in pig screening programs. With the use of porcine islets in clinical trials, special consideration has to be given to the presence of microorganisms in the isolated islet tissue to be used and also to the potential use of encapsulation. It is proposed that microorganisms absent in the donor animals by sensitive microbiological examination do not need to be monitored in the transplant recipient; this will reduce costs and screening requirements. Valid detection assays for donor and manufacturing-derived microorganisms must be established. Special consideration is needed to preempt potential unknown pathogens which may pose a risk to the recipient. This statement summarizes the main achievements in the field since 2009 and focus on issues and solutions with microorganisms other than PERV.
Published: 2016
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30. Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis

Author: Dmitreva J, van Iterson M, Brenda W.J.H. Penninx, Reyhan Sonmez, Michel Georges, Tõnu Esko, Matthias Nauck, Eline Slagboom, Bruce M. Psaty, Urko M. Marigorta, Michel G. Nivard, C Wijmenga, Markus Perola, Joost Verlouw, Jaanika Kronberg-Guzman, Bastiaan T. Heijmans, van Dongen J, Martina Müller-Nurasyid, Yukihide Momozawa, Silva Kasela, Joseph E. Powell, Sina Rüeger, Brandon L. Pierce, Sven Bergmann, van Meurs J, Lude Franke, Uwe Völker, Futao Zhang, Marc Jan Bonder, Z. Kutalik, Frank Beutner, Ilkka Seppälä, Jarno Kettunen, Morris A. Swertz, Harm-Jan Westra, Jan H. Veldink, Hailiang Mei, Joachim Thiery, Jian Yang, Anand Kumar Andiappan, Grant W. Montgomery, Wibowo Arindrarto, Julian C. Knight, Markus Scholz, Mark W. Christiansen, Alexander Teumer, Bernett Lee, Patrick Deelen, Willem H. Ouwehand, Roman Kreuzhuber, Ashis Saha, Andrew A. Brown, Marie-Julie Favé, Eleonora Porcu, Mawusse Agbessi, Samuli Ripatti, Terho Lehtimäki, Jonathan K. Pritchard, Lili Milani, Alexis Battle, Holger Kirsten, Sina A. Gharib, Natalia Pervjakova, Annique Claringbould, Patrick F. Sullivan, Habibul Ahsan, Katharina Schramm, Hanieh Yaghootkar, Oliver Stegle, D.I. Boomsma, Anette Kalnapenkis, Mika Kähönen, Harm Brugge, Lin Tong, Biao Zeng, Holger Prokisch, Kate Downes, Rick Jansen, Peter M. Visscher, Benjamin P. Fairfax, Shuang Li, Urmo Võsa, Emmanouil T. Dermitzakis, Michael Stumvoll, Markus Loeffler, Alvaes I, Rotzchke O, Philip Awadalla, Coen D.A. Stehouwer, Olli T. Raitakari, Gibran Hemani, Peter Kovacs, Peter A C 't Hoen, Timothy M. Frayling, Anke Tönjes, Greg Gibson, Yungil Kim, Kukushkina, Mahmoud Elansary, and Knut Krohn
Subjects: Genetics, 0303 health sciences, Genome-wide association study, Genomics, Quantitative trait locus, Biology, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Expression quantitative trait loci, Trait, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: SummaryWhile many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear.To identify these effects, we performedcis-andtrans-expressionquantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium.We observed thatcis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to usecis-eQTLs to pinpoint causal genes within susceptibility loci.In contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology.We observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.
Published: 2018
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31. Genetic studies of body mass index yield new insights for obesity biology

Author: Locke, Adam E, Kahali, Bratati, Croteau-Chonka, Damien C, Doney, Alex S F, He, Bing, Heikkilä, Outi, Hietala, Kustaa, Kytö, Janne, Lahermo, Päivi, Lehto, Markku, Österholm, Anne-May, Parkkonen, Maija, Pitkäniemi, Janne, Rosengård-Bärlund, Milla, Eklund, Niina, Saraheimo, Markku, Sarti, Cinzia, Söderlund, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena M, Tikkanen, Heikki, Tolonen, Nina, Tryggvason, Karl, Tuomilehto, Jaakko, Estrada, Karol, Wadén, Johan, Gill, Geoffrey V, Prior, Sarah, Guiducci, Candace, Mirel, Daniel B, Taylor, Andrew, Hosseini, Mohsen, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Eury, Elodie, Ladenvall, Claes, Alhenc-Gelas, François, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Maestroni, Silvia, Falhammar, Henrik, Gu, Tianwei, Folkersen, Lasse, Möllsten, Anna, Cimponeriu, Dan, Mihai, Ioana, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L, Nelson, Robert G, Kretzler, Matthias, Fraser, Ross M, Colhoun, Helen M, Panduru, Nicolae Mircea, Gu, Harvest F, Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B, Garcia, Melissa E, Waggott, Daryl, Paterson, Andrew D, Savage, David A, Bain, Stephen C, Martin, Finian, Hirschhorn, Joel N, Godson, Catherine, Florez, Jose C, Groop, Per-Henrik, Maxwell, Alexander P, Geller, Frank, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Giedraitis, Vilmantas, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Y, Demirkan, Ayşe, Den Hertog, Heleen M, Do, Ron, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Gigante, Bruna, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Freitag, Daniel F, Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U, Esko, Tonu, Go, Alan S, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K E, Mangino, Massimo, Golay, Alain, Mihailov, Evelin, Montasser, May E, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Goodall, Alison H, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Gordon, Scott D, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Gorski, Mathias, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doring, Angela, Elliott, Paul, Grabe, Hans-Jörgen, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John J P, Khaw, Kay-Tee, Kim, Eric, Grammer, Tanja B, Klopp, Norman, Komulainen, Pirjo, Kumari, Meena, Langenberg, Claudia, Lehtimaki, Terho, Lin, Shih-Yi, Lindstrom, Jaana, Loos, Ruth J F, Mach, François, McArdle, Wendy L, Gräßler, Jürgen, Meisinger, Christa, Mitchell, Braxton D, Muller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V M, Nsubuga, Rebecca N, Olafsson, Isleifur, Ong, Ken K, Palotie, Aarno, Grönberg, Henrik, Papamarkou, Theodore, Pomilla, Cristina, Pouta, Anneli, Rader, Daniel J, Reilly, Muredach P, Ridker, Paul M, Rivadeneira, Fernando, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Fall, Tove, Scharnagl, Hubert, Seeley, Janet, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J, Tiret, Laurence, Uitterlinden, Andre G, van Pelt, L Joost, Vedantam, Sailaja, Gusto, Gaëlle, Wainwright, Nicholas, Wijmenga, Cisca, Wild, Sarah H, Willemsen, Gonneke, Wilsgaard, Tom, Wilson, James F, Young, Elizabeth H, Zhao, Jing Hua, Adair, Linda S, Arveiler, Dominique, Haessler, Jeffrey, Assimes, Themistocles L, Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O, Boomsma, Dorret I, Borecki, Ingrid B, Bornstein, Stefan R, Bovet, Pascal, Burnier, Michel, Hall, Per, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chen, Yii-Der Ida, Collins, Francis S, Cooper, Richard S, Danesh, John, Dedoussis, George, de Faire, Ulf, Feranil, Alan B, Haller, Toomas, Ferrieres, Jean, Ferrucci, Luigi, Freimer, Nelson B, Gieger, Christian, Groop, Leif C, Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B, Hingorani, Aroon, Hallmans, Goran, Hofman, Albert, Hovingh, G Kees, Hsiung, Chao Agnes, Humphries, Steve E, Hunt, Steven C, Hveem, Kristian, Iribarren, Carlos, Jarvelin, Marjo-Riitta, Jula, Antti, Hartman, Catharina A, Kähönen, Mika, Kaprio, Jaakko, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S, Koudstaal, Peter J, Krauss, Ronald M, Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O, Hassinen, Maija, Laakso, Markku, Lakka, Timo A, Lind, Lars, Lindgren, Cecilia M, Martin, Nicholas G, März, Winfried, McCarthy, Mark I, McKenzie, Colin A, Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D, Munroe, Patricia B, Njølstad, Inger, Pedersen, Nancy L, Power, Chris, Pramstaller, Peter P, Price, Jackie F, Psaty, Bruce M, Quertermous, Thomas, Heard-Costa, Nancy L, Rauramaa, Rainer, Saleheen, Danish, Salomaa, Veikko, Sanghera, Dharambir K, Saramies, Jouko, Schwarz, Peter E H, Sheu, Wayne H-H, Shuldiner, Alan R, Siegbahn, Agneta, Spector, Tim D, Helmer, Quinta, Stefansson, Kari, Strachan, David P, Tayo, Bamidele O, Tremoli, Elena, Uusitupa, Matti, van Duijn, Cornelia M, Vollenweider, Peter, Wallentin, Lars, Wareham, Nicholas J, Hengstenberg, Christian, Whitfield, John B, Wolffenbuttel, Bruce H R, Ordovas, Jose M, Boerwinkle, Eric, Palmer, Colin N A, Thorsteinsdottir, Unnur, Chasman, Daniel I, Rotter, Jerome I, Franks, Paul W, Ripatti, Samuli, Holmen, Oddgeir, Cupples, L Adrienne, Sandhu, Manjinder S, Rich, Stephen S, Boehnke, Michael, Deloukas, Panos, Kathiresan, Sekar, Mohlke, Karen L, Ingelsson, Erik, Abecasis, Gonçalo R, Abecasis, Gonçalo, Hottenga, Jouke-Jan, Caulfield, Mark, Chasman, Dan, Ehret, Georg, Johnson, Andrew, Johnson, Louise, Larson, Martin, Levy, Daniel, James, Alan L, Munroe, Patricia, Newton-Cheh, Christopher, O'Reilly, Paul, Palmas, Walter, Psaty, Bruce, Rice, Kenneth, Smith, Albert, Snider, Harold, Tobin, Martin, Van Duijn, Cornelia, Jeff, Janina M, Verwoert, Germaine, Rice, Kenneth M, Johnson, Andrew D, Smith, Albert V, Tobin, Martin D, Verwoert, Germaine C, Hwang, Shih-Jen, Pihur, Vasyl, O'Reilly, Paul F, Amin, Najaf, Teumer, Alexander, Glazer, Nicole L, Launer, Lenore, Jolley, Jennifer, Aulchenko, Yurii, Heath, Simon, Sõber, Siim, Parsa, Afshin, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Juliusdottir, Thorhildur, Peden, John F, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N, Fava, Cristiano, Kinnunen, Leena, Fox, Ervin R, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Koenig, Wolfgang, Whincup, Peter H, Liu, Yongmei, Shi, Gang, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Nguyen, Khanh-Dung Hoang, Lehtimäki, Terho, Matullo, Giuseppe, Koskenvuo, Markku, Gaunt, Tom R, Onland-Moret, N Charlotte, Cooper, Matthew N, Platou, Carl G P, Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Kratzer, Wolfgang, Braund, Peter S, Kuznetsova, Tatiana, Uiterwaal, Cuno S P M, Adeyemo, Adebowale, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D, Laitinen, Jaana, Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C, Steinle, Nanette I, Grobbee, Diederick E, Arking, Dan E, Kardia, Sharon L, Morrison, Alanna C, Lamina, Claudia, Najjar, Samer, Hadley, David, Brown, Morris J, Connell, John M, Hingorani, Aroon D, Day, Ian N M, Lawlor, Debbie A, Beilby, John P, Lawrence, Robert W, Leander, Karin, Clarke, Robert, Collins, Rory, Hopewell, Jemma C, Ongen, Halit, Dreisbach, Albert W, Li, Yali, Young, J. H., Bis, Joshua C, Viikari, Jorma, Lee, Nanette R, Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Lichtner, Peter, Frayling, Timothy M, Islam, Muhammad, Jafar, Tazeen H, Erdmann, Jeanette, Kulkarni, Smita R, Grässler, Jürgen, Howard, Philip, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Weder, Alan B, Lindström, Jaana, Sun, Yan V, Bergman, Richard N, Scott, Laura J, Stringham, Heather M, Peltonen, Leena, Vartiainen, Erkki, Brand, Stefan-Martin, Kutalik, Zoltán, Lo, Ken Sin, Staessen, Jan A, Wang, Thomas J, Burton, Paul R, Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K, Rudock, Megan E, Lobbens, Stéphane, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairajan, Tripathy, Vikal, Lorbeer, Roberto, Langefeld, Carl D, Rosengren, Annika, Thelle, Dag S, Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, Salako, Tunde, Iwai, Naoharu, Lu, Yingchang, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H-Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Raffel, Leslie J, Yao, Jie, O'Donnell, Chris, Schwartz, Stephen M, Ikram, M Arfan, Longstreth, W. T., Mosley, Thomas H, Seshadri, Sudha, Mahajan, Anubha, Shrine, Nick R G, Wain, Louise V, Morken, Mario A, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A, Rasheed, Asif, Goel, Anuj, Watkins, Hugh, Bakker, Stephan J L, van Gilst, Wiek H, Janipalli, Charles S, Mani, K Radha, Yajnik, Chittaranjan S, McLachlan, Stela, Mattace-Raso, Francesco U S, Oostra, Ben A, Demirkan, Ayse, Lakatta, Edward G, Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J, Menni, Cristina, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Ong, Rick Twee-Hee, Dörr, Marcus, Kroemer, Heyo K, Völker, Uwe, Völzke, Henry, Galan, Pilar, Merger, Sigrun, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Zhai, Guangju, Meschia, James F, Nalls, Michael A, Sharma, Pankaj, Terzic, Janos, Kumar, M J Kranthi, Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E, Fowkes, F Gerald R, Charchar, Fadi J, Guo, Xiuqing, Milani, Lili, Rotimi, Charles, Bots, Michiel L, Brand, Eva, Samani, Nilesh J, Polasek, Ozren, Talmud, Philippa J, Nyberg, Fredrik, Laan, Maris, Moayyeri, Alireza, Palmer, Lyle J, van der Schouw, Yvonne T, Casas, Juan P, Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K, Wong, Tien Y, Tai, E Shyong, Monda, Keri L, Rao, Dabeeru C, Morris, Richard W, Dominiczak, Anna F, Marmot, Michael G, Miki, Tetsuro, Chandak, Giriraj R, Coresh, Josef, Navis, Gerjan, Han, Bok-Ghee, Zhu, Xiaofeng, Melander, Olle, Gyllensten, Ulf B, Mulas, Antonella, Wright, Alan F, Farrall, Martin, Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J G, Altshuler, David, Müller, Gabriele, Rettig, Rainer, Uda, Manuela, Witteman, Jacqueline C M, Vasan, Ramachandran S, Larson, Martin G, Järvelin, Marjo-Riitta, Musk, Arthur W, Caulfield, Mark J, Alizadeh, Behrooz Z, de Boer, Rudolf A, Mägi, Reedik, Boezen, H Marike, Bruinenberg, Marcel, Franke, Lude, Hillege, Hans L, van der Klauw, Melanie M, Ormel, Johan, Postma, Dirkje S, Rosmalen, Judith G M, Nöthen, Markus M, Slaets, Joris P, Stolk, Ronald P, Scott, Robert 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EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Eriksson, J., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Peacock, M., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., van Meurs JB., Weedon, MN., Wichmann, H., Young, L., Bierut, LJ., Boyd, HA., Econs, MJ., Van T'Hooft, Ferdinand M., Njølstad, Inger, Abecasis, Gonçalo R., Barroso, Inɥ, The MIGEN Consortium, Investigator, Casari, GIORGIO NEVIO, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Landsteiner Laboratory, Clinical Haematology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Locke, A, Kahali, B, Berndt, S, Justice, A, Pers, T, Day, F, Powell, C, Vedantam, S, Buchkovich, M, Yang, J, Croteau-Chonka, D, Esko, T, Fall, T, Ferreira, T, Gustafsson, S, Kutalik, Z, Luan, J, Magi, R, Randall, J, Winkler, T, Wood, A, Workalemahu, T, Faul, J, Smith, J, Zhao, J, Zhao, W, Chen, J, Fehrmann, R, Hedman, A, Karjalainen, J, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bolton, J, Bragg-Gresham, J, Buyske, S, Demirkan, A, Deng, G, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Goel, A, Gong, J, Jackson, A, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, 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Investigators, The MuTHER Consortium, The MIGen Consortium, The PAGE Consortium, The ReproGen Consortium, The GENIE Consortium, The International Endogene Consortium, Berndt, Sonja I, Justice, Anne E, Hyppönen, Elina Tuulikki, Epidemiology and Data Science, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes
Subjects: Male, LOCI, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Body Mass Index, Insulin Secretion, Insulin, Age Factor, Adiposity, ddc:616, Adipogenesis, Genetic Predisposition to Disease/genetics, Synapse, 3. Good health, Continental Population Group, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], GENOME-WIDE ASSOCIATIONPROVIDES INSIGHTSGLYCEMIC TRAITSLOCIMETAANALYSISVARIANTSINDIVIDUALSHIPPOCAMPALARCHITECTURETOPIRAMATE, ddc:500, Adipogenesis/genetics, Single Nucleotide/genetics, Age Factors, Continental Population Groups, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Glutamic Acid, Humans, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses, Genome-Wide Association Study, Multidisciplinary, genetics [Adiposity], Human, Socio-culturale, genetics [Energy Metabolism], ta3111, genetic, body mass index, obesity, SDG 3 - Good Health and Well-being, GLYCEMIC TRAITS, genetics [Continental Population Groups], Genetic variability, Polymorphism, GENOME-WIDE ASSOCIATION, genetics [Adipogenesis], METAANALYSIS, Genetic association, Adipogenesi, genetics [Quantitative Trait Loci], ta1184, metabolism [Glutamic Acid], ta1182, PATHWAYS, metabolism [Synapses], ta3121, medicine.disease, metabolism [Insulin], Adiposity/genetics, Clinical Medicine, Quantitative Trait Loci/genetics, Body mass index, HUMAN HEIGHT, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Synapses/metabolism, Medizin, Obesity/genetics, Bioinformatics, genetic basis, Obesity/metabolism, genetics [Obesity], body mass index (BMI), genetics [Genetic Predisposition to Disease], ethnology [Europe], 2. Zero hunger, Genetics, ARCHITECTURE, Genetics of obesity, Medicine (all), Single Nucleotide, Polymorphism, Single Nucleotide/genetics, Insulin/metabolism/secretion, Glutamic Acid/metabolism, genetics [Polymorphism, Single Nucleotide], EXPRESSION, Insulin/metabolism, PROVIDES INSIGHTS, genetics [Racial Groups], Biology, Obesity/genetics/metabolism, Europe/ethnology, metabolism [Obesity], Mendelian randomization, medicine, Energy Metabolism/genetics, body mass, genetic analysis, obesity, Klinisk medicin
Abstract: Item does not contain fulltext Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for approximately 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
Published: 2015
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32. New genetic loci link adipose and insulin biology to body fat distribution

Author: Shungin, Dmitry, Winkler, Thomas W, Workalemahu, Tsegaselassie, Hartman, Catharina A, Duncan, Emma L, Ntzani, Evangelia E, Oei, Ling, Albagha, Omar M E, Amin, Najaf, Kemp, John P, Koller, Daniel L, Li, Guo, Liu, Ching-Ti, Minster, Ryan L, Hassinen, Maija, Moayyeri, Alireza, Vandenput, Liesbeth, Willner, Dana, Xiao, Su-Mei, Yerges-Armstrong, Laura M, Zheng, Hou-Feng, Alonso, Nerea, Eriksson, Joel, Kammerer, Candace M, Kaptoge, Stephen K, Hayward, Caroline, Leo, Paul J, Thorleifsson, Gudmar, Wilson, Scott G, Wilson, James F, Aalto, Ville, Alen, Markku, Aragaki, Aaron K, Aspelund, Thor, Center, Jacqueline R, Dailiana, Zoe, Heikkilä, Kauko, Duggan, David J, Garcia, Melissa, Garcia-Giralt, Natàlia, Giroux, Sylvie, Hallmans, Göran, Hocking, Lynne J, Husted, Lise Bjerre, Jameson, Karen A, Khusainova, Rita, Kim, Ghi Su, Herzig, Karl-Heinz, Kooperberg, Charles, Koromila, Theodora, Kruk, Marcin, Laaksonen, Marika, Lacroix, Andrea Z, Lee, Seung Hun, Leung, Ping C, Lewis, Joshua R, Masi, Laura, Mencej-Bedrac, Simona, Helmer, Quinta, Nguyen, Tuan V, Nogues, Xavier, Patel, Millan S, Prezelj, Janez, Rose, Lynda M, Scollen, Serena, Siggeirsdottir, Kristin, Smith, Albert V, Svensson, Olle, Trompet, Stella, Hillege, Hans L, Trummer, Olivia, van Schoor, Natasja M, Woo, Jean, Zhu, Kun, Balcells, Susana, Brandi, Maria Luisa, Buckley, Brendan M, Cheng, Sulin, Christiansen, Claus, Cooper, Cyrus, Holmen, Oddgeir, Dedoussis, George, Ford, Ian, Frost, Morten, Goltzman, David, González-Macías, Jesús, Kähönen, Mika, Karlsson, Magnus, Khusnutdinova, Elza, Koh, Jung-Min, Kollia, Panagoula, Hunt, Steven C, Langdahl, Bente Lomholt, Leslie, William D, Lips, Paul, Ljunggren, Östen, Lorenc, Roman S, Marc, Janja, Mellström, Dan, Obermayer-Pietsch, Barbara, Olmos, José M, Pettersson-Kymmer, Ulrika, Isaacs, Aaron, Reid, David M, Riancho, José A, Ridker, Paul M, Rousseau, François, Slagboom, P Eline, Tang, Nelson L S, Urreizti, Roser, Van Hul, Wim, Viikari, Jorma, Zarrabeitia, María T, Wu, 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Olivier, Mychaleckyj, Josyf C, Gräßler, Jürgen, Grewal, Jagvir, Curhan, Gary, Hallan, Stein, Shlipak, Michael G, Hallmans, Goran, Kao, W. H. 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Haessler, J., Kocarnik, J., Lin, Y., Jackson, R., Duggan, D., Kuller, L., Stolk, L., He, C., Sulem, P., Barbalic, M., Broer, L., Byrne, EM., Gudbjartsson, DF., McArdle, PF., Porcu, E., van Wingerden, S., Zhuang, W., Albrecht, E., Alizadeh, BZ., Lauc, LB., Broekmans, FJ., Burri, A., Chanock, SJ., Chen, C., Corre, T., Coviello, AD., d'Adamo, P., Davies, G., Deary, IJ., Ebrahim, S., Fauser, BC., Ferreli, L., Folsom, AR., Garcia, ME., Hall, P., Haller, T., Hankinson, SE., Hass, M., Heath, AC., Janssens, AC., Keyzer, J., Lahti, J., Lai, S., Laisk, T., Laven, JS., Liu, J., Lopez, LM., Louwers, YV., Marongiu, M., Klaric, IM., Masciullo, C., McKnight, B., Medland, SE., Melzer, D., Newman, AB., Paré, G., Peeters, PH., Plump, AS., Pop, VJ., Räikkönen, K., Salumets, A., Smith, JA., Stacey, SN., Starr, JM., Stathopoulou, MG., Tenesa, A., Thorand, B., Tryggvadottir, L., Tsui, K., van Dam RM., van Gils CH., van Nierop, P., Vink, JM., Voorhuis, M., Wallaschofski, H., Widen, E., Wijnands-van Gent CJ., Zgaga, L., Zygmunt, M., Arnold, AM., Buring, JE., Crisponi, L., Demerath, EW., Hunter, DJ., Schlessinger, D., Murray, A., Murabito, JM., Visser, JA., Lunetta, KL., Elks, CE., Cousminer, DL., Feenstra, B., Lin, P., van Wingerden SW., Smith, EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., Weedon, MN., Wichmann, H., Young, L., Zhuang, WV., Bierut, LJ., Boyd, HA., Department of Clinical Sciences, Lund University [Lund], Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Department of Odontology, Umeå University, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Sciences, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Laboratory of Image Science and Technology [Nanjing] (LIST), Southeast University [Jiangsu]-School of Computer Science and Engineering, Limnology, Ecology, Estonian Genome and Medicine, University of Tartu, Institute of Molecular and Cell Biology, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Institute of Medical Informatics, Biometry and Epidemiology, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, King‘s College London, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Molecular Genetics Section, University of Groningen [Groningen]-University Medical Centre Groningen, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Department of Pharmacy Sciences, Creighton University Medical Center, Medical Department III, Universität Leipzig, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Epidemiology, Erasmus Medical Centre, Netherlands Genomics Initiative (NGI), Netherlands Genomics Initiative, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Department of Public Health and Clinical Medicine, Medstar Research Institute, Genetics and Pathology, Finnish Institute of Occupational Health, Epidemiology, University Medical Centre Groningen, Departments of Microbiology & Molecular Genetics and Molecular Biology & Biochemistry, University of California [Irvine] (UC Irvine), Department of Odontology, Cariology, Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Division of Cardiology, Geneva University Hospital (HUG), Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Anaesthesia and Intensive care, Royal Aberdeen Childrens Hospital, UCL Institute of neurology, UCL Institute of Neurology, Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Departments of Epidemiology and Nutrition, Harvard School of Public Health, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University Hospital, Department of Genetics, University of Groningen [Groningen], deCODE Genetics, deCODE genetics [Reykjavik], Pediatric Pulmonology, Allergology & Epidemiology, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG)-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, Department of Nutrition-Dietetics, Harokopio University of Athens, Yale School of Medicine [New Haven, Connecticut] (YSM), National Heart and Lung Institute (NHLI), Imperial College London, Queensland Institute of Medical Research, Concord Hospital, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Dept. Atherosclerose, Kidney Center, University Medical Center Groningen [Groningen] (UMCG), Department of Public Health & Primary Care, University of Cambridge [UK] (CAM), Department of cardiology, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Internal Medicine, University of Pisa - Università di Pisa, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Health Sciences Research Institute, Warwick, Department of Nephrology, University Medical Center, University of Groningen, Institute of Genetic Epidemiology, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Executive Board, Polycystic Kidney Disease Charity (PKD Charity)-Ciliopathy Alliance-International Alliance, Department of Zoology, University of Otago [Dunedin, Nouvelle-Zélande], Institute for Community Medicine, Department Epidemiology of Health Care and Community Health, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, 5 University Street, Centre for Paediatric Epidemiology and Biostatistics, University College of London [London] (UCL), MRC Centre for Epidemiology of Child Health, UCL Institute of Child Health, Unit for Molecular Epidemiology, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Department of Epidemiology and Biostatistics, Department of Life Course and Services, National Institute for Health and Welfare [Helsinki], Department of Epidemiology and Public Health, Queen's University [Belfast] (QUB), Interdisciplinary Center of Clinical Research, Department of Physiology, University of Eastern Finland-Institute of Biomedicine, University of Hawai‘i [Mānoa] (UHM), Department of Clinical Chemistry, University of Tampere [Finland]-Tampere University Hospital, Chronic Disease Epidemiology and Prevention Unit, Université Laval [Québec] (ULaval), Centre for Bone and Arthritis Research, University of Gothenburg (GU)-Institute of Medicine, Interdisciplinary Center for Psychiatric Epidemiology, Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Department of Clinical Physiology, Turku University Hospital (TYKS), Brigham and Women's Hospital [Boston], Department of Chronic Disease Prevention, Department of Cardiovascular Sciences [Leicester], University of Leicester, Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Maastricht University [Maastricht], Institute of Social and Preventive Medicine, Lausanne University Hospital, Carl Gustav Carus University Hospital, Recherches en Psychopathologie, nouveaux symptômes et lien social (EA 4050), Université de Poitiers-Université de Brest (UBO)-Université Catholique de l'Ouest (UCO)-Université de Rennes 2 (UR2), Institut de biologie de Lille - UMS 3702 (IBL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Department of child and adolescent psychiatry, Institute for Medical Informatics, Biometry, and Epidemiology, MRC National Survey of Health and Development, MRC Unit for Lifelong Health and Ageing, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Peter MacCallum Cancer Center, Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, Department of Pediatrics, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Department of Public Health, South Ostrobothnia Central Hospital, Department of Clinical and Preventive Medicine, Danube-University Krems, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, MRC epidemiology Unit, Institute of Epidemiology, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Oncology, Queensland Brain Institute, University of Queensland [Brisbane], Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital [Boston], Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Metabolic Disease Group, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Epidemiology Unit, Addenbrooke's Hospital-Medical Research Council (MRC), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Endocrinology and Metabolism, The Churchill Hospital-Oxford Centre for Diabetes, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Lund University Diabetes Centre-Lund University [Lund], Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers, Technical University of Denmark [Lyngby] (DTU), Université de Lausanne (UNIL), Universität Duisburg-Essen [Essen], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), University of California [Berkeley], University of California-University of California, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universität Leipzig [Leipzig], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of California [Irvine] (UCI), German Research Center for Environmental Health, University of Bonn, Czech Academy of Sciences [Prague] (ASCR), Yale University School of Medicine, University of Oxford [Oxford], German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Laval University, Laval University [Québec], Turku University Hospital, Lausanne university hospital, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Helmholtz-Zentrum München (HZM), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Internal Medicine, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Medical Informatics, Obstetrics & Gynecology, Lund University [Lund]-Lund University Diabetes Centre, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institute of Medicine-University of Gothenburg (GU), Signalisation et Transports Ioniques Membranaires ( STIM ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), Technical University of Denmark [Lyngby] ( DTU ), Laboratory of Image Science and Technology [Nanjing] ( LIST ), Department of Medical Epidemiology and Biostatistics ( MEB ), University of Lausanne, Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Erasmus MC, Space Sciences Laboratory [Berkeley] ( SSL ), Génomique Intégrative et Modélisation des Maladies Métaboliques ( EGID ), Université de Lille-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), University of Leipzig, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institute of Epidemiology [Neuherberg] ( EPI ), University of California [Irvine] ( UCI ), Génétique des maladies multifactorielles ( GMM ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Geneva University Hospital ( HUG ), Bonn Universität [Bonn], Indian Institute of Technology Kanpur ( IIT Kanpur ), The University of North Carolina at Chapel Hill, Université de Bonn, Wellcome Trust Sanger Institute, Harvard University School of Public Health, Czech Academy of Sciences [Prague] ( ASCR ), deCODE genetics, University of Groningen [Groningen]-University Medical Center Groningen-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, Yale School of Medicine, National Heart and Lung Institute ( NHLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, University Medical Center Groningen, University of Cambridge [UK] ( CAM ), Wellcome Trust Centre for Human Genetics, University of Pisa [Pisa], University of Cambridge [UK] ( CAM ) -Institute of Metabolic Science, German Research Center for Environmental Health-Helmholtz-Zentrum München ( HZM ), University of Otago, University of Greifswald, University College of London [London] ( UCL ), National Institute for Health and Welfare, Queen's University [Belfast] ( QUB ), University of Hawaii at Manoa ( UHM ), University of Gothenburg ( GU ) -Institute of Medicine, Recherches en Psychopathologie, nouveaux symptômes et lien social ( EA 4050 ), Université de Poitiers-Université de Brest ( UBO ) -Université Catholique de l'Ouest-Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Institut de biologie de Lille - IBL ( IBLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Finland Institute for Molecular Medicine ( FIMM ), Georgia Prevention Institute, Netherlands Consortium for Healthy Aging, Helmholtz-Zentrum München ( HZM ), National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Massachusetts General Hospital, Children's Hospital, Boston, Broad Institute, Cambridge, MA, The University of North Carolina at Chapel Hill-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Shungin D, Winkler TW, Adipogen, Consortium, Cardiogramplusc4d, Consortium, Ckdgen, Consortium, Gefos, Consortium, Genie, Consortium, Glgc, Icbp, International, Endogene Consortium, Lifelines, Cohort Study, Magic, Investigator, Muther, Consortium, Consortium, Page, ReproGen Consortium, Amouyel P, D'Adamo, ADAMO PIO, Gasparini, Paolo, Shungin, Dmitry, Winkler, Thomas W, Croteau-Chonka, Damien C, Ferreira, Teresa, Hypponen, Elina, Mohlke, Karen L, ADIPOGEN Consortium, Int Endogene Consortium, Lee Kong Chian School of Medicine (LKCMedicine), Epidemiologie, RS: CARIM - R3.02 - Hypertension and target organ damage, Université de Tours-Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Shungin, D, Winkler, T, Croteau Chonka, D, Ferreira, T, Locke, A, Mägi, R, Strawbridge, R, Pers, T, Fischer, K, Justice, A, Workalemahu, T, Wu, J, Buchkovich, M, Heard Costa, N, Roman, T, Drong, A, Song, C, Gustafsson, S, Day, F, Esko, T, Fall, T, Kutalik, Z, Luan, J, Randall, J, Scherag, A, Vedantam, S, Wood, A, Chen, J, Fehrmann, R, Karjalainen, J, Kahali, B, Liu, C, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bragg Gresham, J, Buyske, S, Demirkan, A, Ehret, G, Feitosa, M, Goel, A, Jackson, A, Johnson, T, Kleber, M, Kristiansson, K, Mangino, M, Leach, I, Medina Gomez, C, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Stanca'Kova', A, Sung, Y, Tanaka, T, Teumer, A, Van Vliet Ostaptchouk, J, Yengo, L, Zhang, W, Albrecht, E, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Böhringer, S, Bonnet, F, Böttcher, Y, Bruinenberg, M, Carba, D, Caspersen, I, Clarke, R, Daw, E, Deelen, J, Deelman, E, Delgado, G, Doney, A, Eklund, N, Erdos, M, Estrada, K, Eury, E, Friedrich, N, Garcia, M, Giedraitis, V, Gigante, B, Go, A, Golay, A, Grallert, H, Grammer, T, Gräsler, J, Grewal, J, Groves, C, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heikkilä, K, Herzig, K, Helmer, Q, Hillege, H, Holmen, O, Hunt, S, Isaacs, A, Ittermann, T, James, A, Johansson, I, Juliusdottir, T, Kalafati, I, Kinnunen, L, Koenig, W, Kooner, I, Kratzer, W, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Menni, C, Merger, S, Mihailov, E, Milani, L, Mills, R, Moayyeri, A, Monda, K, Mooijaart, S, Mühleisen, T, Mulas, A, Müller, G, Müller Nurasyid, M, Nagaraja, R, Nalls, M, Narisu, N, Glorioso, N, Nolte, I, Olden, M, Rayner, N, Renstrom, F, Ried, J, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Sennblad, B, Seufferlein, T, Sitlani, C, Smith, A, Stirrups, K, Stringham, H, Sundström, J, Swertz, M, Swift, A, Syvänen, A, Tayo, B, Thorand, B, Thorleifsson, G, Tomaschitz, A, Troffa, C, Van Oort, F, Verweij, N, Vonk, J, Waite, L, Wennauer, R, Wilsgaard, T, Wojczynski, M, Wong, A, Zhang, Q, Zhao, J, Brennan, E, Choi, M, Eriksson, P, Folkersen, L, Franco Cereceda, A, Gharavi, A, Hedman, A, Hivert, M, Huang, J, Kanoni, S, Karpe, F, Keildson, S, Kiryluk, K, Liang, L, Lifton, R, Ma, B, Mcknight, A, Mcpherson, R, Metspalu, A, Min, J, Moffatt, M, Montgomery, G, Murabito, J, Nicholson, G, Nyholt, D, Olsson, C, Perry, J, Reinmaa, E, Salem, R, Sandholm, N, Schadt, E, Scott, R, Stolk, L, Vallejo, E, Westra, H, Zondervan, K, Amouyel, P, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Blangero, J, Brown, M, Burnier, M, Campbell, H, Chakravarti, A, Chines, P, Claudi Boehm, S, Collins, F, Crawford, D, Danesh, J, De Faire, U, De Geus, E, Dörr, M, Erbel, R, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Forouhi, N, Forrester, T, Franco, O, Gansevoort, R, Gieger, C, Gudnason, V, Haiman, C, Harris, T, Hattersley, A, Heliövaara, M, Hicks, A, Hingorani, A, Hoffmann, W, Hofman, A, Homuth, G, Humphries, S, Hyppönen, E, Illig, T, Jarvelin, M, Johansen, B, Jousilahti, P, Jula, A, Kaprio, J, Kee, F, Keinanen Kiukaanniemi, S, Kooner, J, Kooperberg, C, Kovacs, P, Kraja, A, Kumari, M, Kuulasmaa, K, Kuusisto, J, Lakka, T, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lyssenko, V, Männistö, S, Marette, A, Matise, T, Mckenzie, C, Mcknight, B, Musk, A, Möhlenkamp, S, Morris, A, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Palmer, L, Penninx, B, Peters, A, Pramstaller, P, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ridker, P, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schwarz, P, Shuldiner, A, Staessen, J, Steinthorsdottir, V, Stolk, R, Strauch, K, Tönjes, A, Tremblay, A, Tremoli, E, Vohl, M, Völker, U, Vollenweider, P, Wilson, J, Witteman, J, Adair, L, Bochud, M, Boehm, B, Bornstein, S, Bouchard, C, Cauchi, S, Caulfield, M, Chambers, J, Chasman, D, Cooper, R, Dedoussis, G, Ferrucci, L, Froguel, P, Grabe, H, Hamsten, A, Hui, J, Hveem, K, Jöckel, K, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, März, W, Munroe, P, Njolstad, I, Oostra, B, Pedersen, N, Perola, M, Pe'Russe, L, Peters, U, Power, C, Quertermous, T, Rauramaa, R, Rivadeneira, F, Saaristo, T, Saleheen, D, Sinisalo, J, Slagboom, P, Snieder, H, Spector, T, Thorsteinsdottir, U, Stumvoll, M, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Van Der Harst, P, Veronesi, G, Walker, M, Wareham, N, Watkins, H, Wichmann, H, Abecasis, G, Assimes, T, Berndt, S, Boehnke, M, Borecki, I, Deloukas, P, Franke, L, Frayling, T, Groop, L, Hunter, D, Kaplan, R, O'Connell, J, Qi, L, Schlessinger, D, Strachan, D, Stefansson, K, Van Duijn, C, Willer, C, Visscher, P, Yang, J, Hirschhorn, J, Zillikens, M, Mccarthy, M, Speliotes, E, North, K, Fox, C, Barroso, I, Franks, P, Ingelsson, E, Heid, I, Loos, R, Cupples, L, Lindgren, C, Mohlke, K, Dastani, Z, Timpson, N, Yuan, X, Henneman, P, Kizer, J, Lyytikainen, L, Fuchsberger, C, Small, K, Coassin, S, Lohman, K, Pankow, J, Uh, H, Wu, Y, Bidulescu, A, Rasmussen Torvik, L, Greenwood, C, Ladouceur, M, Grimsby, J, Manning, A, Mooser, V, Kapur, K, Frants, R, Willemsvan vanDijk, K, Willems, S, Psaty, B, Tracy, R, Brody, J, Chen, I, Viikari, J, Kähönen, M, Evans, D, St Pourcain, B, Sattar, N, Carlson, O, Egan, J, van Heemst, D, Kedenko, L, Nuotio, M, Loo, B, Kanaya, A, Haun, M, Klopp, N, Katsareli, E, Couper, D, Duncan, B, Kloppenburg, M, Borja, J, Musani, S, Guo, X, Semple, R, Teslovich, T, Allison, M, Redline, S, Buxbaum, S, Meulenbelt, I, Ballantyne, C, Hu, F, Paulweber, B, Florez, J, Smith, G, Siscovick, D, Kronenberg, F, van Duijn, C, Waterworth, D, Meigs, J, Dupuis, J, Richards, J, Willenborg, C, Thompson, J, Erdmann, J, Goldstein, B, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Lundmark, P, Lyytikäinen, L, Rafelt, S, Tikkanen, E, Van Zuydam, N, Voight, B, Ziegler, A, Altshuler, D, Balmforth, A, Braund, P, Burgdorf, C, Cox, D, Dimitriou, M, Do, R, El Mokhtari, N, Fontanillas, P, Hager, J, Han, B, Kang, H, Kessler, T, Knowles, J, Kolovou, G, Langford, C, Lokki, M, Lundmark, A, Meisinger, C, Melander, O, Maouche, S, Nikus, K, Peden, J, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Basart, H, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Gauguier, D, Goodall, A, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kim, H, Laaksonen, R, Ouwehand, W, Parish, S, Park, J, Rader, D, Shah, S, Stark, K, Trégouët, D, Virtamo, J, Wallentin, L, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Hovingh, G, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, O'Donnell, C, Reilly, M, Collins, R, Kathiresan, S, Roberts, R, Schunkert, H, Pattaro, C, Köttgen, A, Garnaas, M, Böger, C, Chen, M, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, M, O'Seaghdha, C, Glazer, N, Struchalin, M, Li, G, Johnson, A, Gierman, H, Hwang, S, Atkinson, E, Cornelis, M, Chouraki, V, Holliday, E, Sorice, R, Deshmukh, H, Ulivi, S, Chu, A, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Launer, L, Aspelund, T, Eiriksdottir, G, Mitchell, B, Schmidt, H, Cavalieri, M, Rao, M, de Andrade, M, Turner, S, Ding, J, Andrews, J, Freedman, B, Döring, A, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, H, Igl, W, Zaboli, G, Wild, S, Wright, A, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Endlich, K, Ernst, F, Kroemer, H, Nauck, M, Stracke, S, Völzke, H, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, J, Ruggiero, D, Bergmann, S, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Robino, A, Giulianini, F, Krämer, B, Portas, L, Ford, I, Buckley, B, Adam, M, Thun, G, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, S, Gasparini, P, Pirastu, M, Jukema, J, Probst Hensch, N, Toniolo, D, Coresh, J, Schmidt, R, Kardia, S, Curhan, G, Gyllensten, U, Franke, A, Rettig, R, Parsa, A, Goessling, W, Kao, W, de Boer, I, Peralta, C, Akylbekova, E, Kramer, H, van der Harst, P, Arking, D, Franceschini, N, Hernandez, D, Townsend, R, Lumley, T, Kestenbaum, B, Haritunians, T, Waeber, G, Lu, X, Leak, T, Aasarød, K, Skorpen, F, Baumert, J, Devuyst, O, Mychaleckyj, J, Hallan, S, Navis, G, Shlipak, M, Bull, S, Paterson, A, Rotter, J, Beckmann, J, Dreisbach, A, Styrkarsdottir, U, Evangelou, E, Hsu, Y, Duncan, E, Ntzani, E, Oei, L, Albagha, O, Kemp, J, Koller, D, Minster, R, Vandenput, L, Willner, D, Xiao, S, Yerges Armstrong, L, Zheng, H, Alonso, N, Kammerer, C, Kaptoge, S, Leo, P, Wilson, S, Aalto, V, Alen, M, Aragaki, A, Center, J, Dailiana, Z, Duggan, D, Garcia Giralt, N, Giroux, S, Hocking, L, Husted, L, Jameson, K, Khusainova, R, Kim, G, Koromila, T, Kruk, M, Laaksonen, M, Lacroix, A, Lee, S, Leung, P, Lewis, J, Masi, L, Mencej Bedrac, S, Nguyen, T, Nogues, X, Patel, M, Prezelj, J, Scollen, S, Siggeirsdottir, K, Svensson, O, Trummer, O, van Schoor, N, Woo, J, Zhu, K, Balcells, S, Brandi, M, Cheng, S, Christiansen, C, Cooper, C, Frost, M, Goltzman, D, González Macías, J, Karlsson, M, Khusnutdinova, E, Koh, J, Kollia, P, Langdahl, B, Leslie, W, Lips, P, Ljunggren, Ö, Lorenc, R, Marc, J, Mellström, D, Obermayer Pietsch, B, Olmos, J, 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Kaleebu, P, Kastelein, J, Kim, E, Komulainen, P, Lin, S, Nieminen, T, Nsubuga, R, Olafsson, I, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Ruokonen, A, Seeley, J, Silander, K, Stančáková, A, Tiret, L, van Pelt, L, Wainwright, N, Wijmenga, C, Willemsen, G, Young, E, Bennett, F, Boomsma, D, Bovet, P, Chen, Y, Feranil, A, Freimer, N, Hsiung, C, Järvelin, M, Kesäniemi, A, Koudstaal, P, Krauss, R, Kyvik, K, Martin, N, Meneton, P, Moilanen, L, Njølstad, I, Price, J, Sanghera, D, Sheu, W, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Rich, S, Johnson, L, Larson, M, Levy, D, Newton Cheh, C, O'Reilly, P, Palmas, W, Rice, K, Snider, H, Tobin, M, Verwoert, G, Pihur, V, Heath, S, Sõber, S, Arora, P, Zhang, F, Lucas, G, Milaneschi, Y, Parker, A, Fava, C, Fox, E, Go, M, Sjögren, M, Vinay, D, Alexander, M, Tabara, Y, Shaw Hawkins, S, Whincup, P, Shi, G, Seielstad, M, Sim, X, Nguyen, K, Matullo, G, Gaunt, T, Onland Moret, N, Cooper, M, Platou, C, Org, E, Hardy, R, Dahgam, S, Palmen, J, Kuznetsova, T, Uiterwaal, C, Adeyemo, A, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, N, Chang, Y, Steinle, N, Grobbee, D, Morrison, A, Najjar, S, Hadley, D, Connell, J, Day, I, Lawlor, D, Lawrence, R, Ongen, H, Li, Y, Young, J, Bis, J, Chaturvedi, N, Islam, M, Jafar, T, Kulkarni, S, Grässler, J, Howard, P, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Weder, A, Sun, Y, Scott, L, Peltonen, L, Vartiainen, E, Brand, S, Wang, T, Burton, P, Artigas, M, Dong, Y, Wang, X, Zhu, H, Rudock, M, Heckbert, S, Smith, N, Wiggins, K, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, C, Rosengren, A, Thelle, D, Corsi, A, Singleton, A, Hilton, G, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Cho, Y, Scott, J, Sehmi, J, Hedblad, B, Nilsson, P, Stanèáková, A, Raffel, L, Yao, J, Schwartz, S, Ikram, M, Longstreth W., J, Mosley, T, Seshadri, S, Shrine, N, Wain, L, Morken, M, Laitinen, J, Zitting, P, Cooper, J, van Gilst, W, Janipalli, C, Mani, K, Yajnik, C, Mattace Raso, F, Lakatta, E, Orru, M, Scuteri, A, Ala Korpela, M, Kangas, A, Soininen, P, Tukiainen, T, Würtz, P, Ong, R, Galan, P, Hercberg, S, Lathrop, M, Zelenika, D, Zhai, G, Meschia, J, Sharma, P, Terzic, J, Kumar, M, Denniff, M, Zukowska Szczechowska, E, Wagenknecht, L, Fowkes, F, Charchar, F, Rotimi, C, Bots, M, Brand, E, Talmud, P, Nyberg, F, Laan, M, van der Schouw, Y, Casas, J, Vineis, P, Ganesh, S, Wong, T, Tai, E, Morris, R, Dominiczak, A, Marmot, M, Miki, T, Chandak, G, Zhu, X, Elosua, R, Soranzo, N, Sijbrands, E, Uda, M, Vasan, R, Anderson, C, Gordon, S, Guo, Q, Henders, A, Lambert, A, Kraft, P, Kennedy, S, Macgregor, S, Missmer, S, Painter, J, Roseman, F, Treloar, S, Wallace, L, Alizadeh, B, de Boer, R, Boezen, H, van der Klauw, M, Ormel, J, Postma, D, Rosmalen, J, Slaets, J, Lagou, V, Welch, R, Wheeler, E, Rehnberg, E, Lecoeur, C, Johnson, P, Hottenga, J, Salo, P, Bielak, L, Zhao, W, Horikoshi, M, Navarro, P, Chen, H, Rybin, D, Song, K, An, P, Marullo, L, Jansen, H, Edkins, S, Varga, T, Oksa, H, Antonella, M, Kong, A, Herder, C, Antti, J, Miljkovic, I, Atalay, M, Kiess, W, Smit, J, Campbell, S, Fowkes, G, Rathmann, W, Maerz, W, Watanabe, R, de Geus, E, Toenjes, A, Peyser, P, Körner, A, Cucca, F, Balkau, B, Bouatia Naji, N, Ahmadi, K, Ainali, C, Bataille, V, Bell, J, Buil, A, Dermitzakis, E, Dimas, A, Durbin, R, Glass, D, Hassanali, N, Hedman, Å, Ingle, C, Knowles, D, Krestyaninova, M, Lowe, C, Meduri, E, di Meglio, P, Montgomery, S, Nestle, F, Nica, A, Nisbet, J, O'Rahilly, S, Parts, L, Potter, S, Sekowska, M, Shin, S, Surdulescu, G, Travers, M, Tsaprouni, L, Tsoka, S, Wilk, A, Higashio, J, Williams, R, Nato, A, Ambite, J, Manolio, T, Hindorff, L, Heiss, G, Taylor, K, Avery, C, Graff, M, Lin, D, Quibrera, M, Cochran, B, Kao, L, Umans, J, Cole, S, Maccluer, J, Person, S, Gross, M, Fornage, M, Durda, P, Jenny, N, Patsy, B, Arnold, A, Buzkova, P, Haines, J, Murdock, D, Glenn, K, 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Smith, J, Stacey, S, Starr, J, Stathopoulou, M, Tenesa, A, Tryggvadottir, L, Tsui, K, van Dam, R, van Gils, C, van Nierop, P, Vink, J, Voorhuis, M, Wallaschofski, H, Widen, E, Wijnands van Gent, C, Zgaga, L, Zygmunt, M, Buring, J, Crisponi, L, Demerath, E, Murray, A, Visser, J, Lunetta, K, Elks, C, Cousminer, D, Feenstra, B, Lin, P, Smith, E, Warrington, N, Alavere, H, Berenson, G, Blackburn, H, Busonero, F, Chen, W, Easton, D, Foroud, T, Geller, F, Kilpeläinen, T, Li, S, Melbye, M, Murray, J, Murray, S, Ness, A, Northstone, K, Pennell, C, Pharoah, P, Rafnar, T, Rice, J, Ring, S, Schork, N, Segrè, A, Sovio, U, Srinivasan, S, Tammesoo, M, Tyrer, J, Weedon, M, Young, L, Bierut, L, Boyd, H, Psychiatry, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes
Subjects: Adipose Tissue/metabolism, Male, genetic association, subcutaneous fat, Transcription, Genetic, Adipocytes, Adipogenesis, Adipose Tissue, Age Factors, Body Mass Index, Continental Population Groups, Epigenesis, Genetic, Europe, Female, Genome, Human, Humans, Insulin, Insulin Resistance, Models, Biological, Neovascularization, Physiologic, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sex Characteristics, Waist-Hip Ratio, Body Fat Distribution, Genome-Wide Association Study, Multidisciplinary, Insulin Resistance/genetics, Genome-wide association study, Continental Population Groups/genetics, genetic analysis, heritability, gene cluster, Science::Biological sciences::Human anatomy and physiology [DRNTU], 0302 clinical medicine, high density lipoprotein cholesterol, Models, genetics [Insulin Resistance], histone modification, Age Factor, insulin receptor, 0303 health sciences, Adipocyte, Human/genetics, CARDIOGRAMplusC4D Consortium, ADIPOGENIC DIFFERENTIATION, genetic correlation, body fat, Continental Population Group, priority journal, 5 trisphosphate 3 phosphatase, GEFOS Consortium, meta analysis (topic), Science & Technology - Other Topics, ddc:500, transcription regulation, Adipogenesis/genetics, Single Nucleotide/genetics, Human, medicine.medical_specialty, Waist, phosphatidylinositol 3, European, ta3111, genetic regulation, Article, developmental biology, 03 medical and health sciences, MAGIC Investigators, transcription initiation site, SDG 3 - Good Health and Well-being, Genetic, genomics, GLYCEMIC TRAITS, genetics [Continental Population Groups], Polymorphism, GENOME-WIDE ASSOCIATION, Physiologic, genetics [Adipogenesis], Adipocytes/metabolism, Europe/ethnology, Genome, Human/genetics, Insulin/metabolism, Neovascularization, Physiologic/genetics, Obesity/genetics, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Transcription, Genetic/genetics, Genetic/genetics, Adipogenesi, Science & Technology, adiponectin, [ SDV ] Life Sciences [q-bio], vasculotropin, genetics [Quantitative Trait Loci], ta1184, Racial Groups, ta1182, gene mapping, ta3121, triacylglycerol blood level, medicine.disease, Biological, major clinical study, amino acid sequence, metabolism [Insulin], Endocrinology, metabolism [Adipocytes], genetic loci, insulin, body fat, GLGC, International Endogene Consortium, metabolism [Adipose Tissue], Body mass index, HUMAN HEIGHT, Epigenesis, LifeLines Cohort Study, ReproGen Consortium, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, tissue level, Physiologic/genetics, [SDV]Life Sciences [q-bio], Medizin, Adipose tissue, low density lipoprotein cholesterol, PAGE Consortium, COMMON SNPS, angiogenesis, Waist–hip ratio, genetics [Obesity], MESH: Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism* Age Factors Body Fat Distribution* Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study* Humans Insulin/metabolism* Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics* Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio, single nucleotide polymorphism, fat, genetic variability, molecular biology, body mass index (BMI), ethnology [Europe], peroxisome proliferator activated receptor, 2. Zero hunger, Genetics, Genome, Single Nucleotide, waist circumference, insulin, phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase, triacylglycerol, vasculotropin, developmental biology, gene expression, genome, numerical model, adipocyte, adipose tissue, body fat distribution, body mass, female, gene locus, gene structure, hip circumference, human, insulin resistance, lipoprotein blood level, male, obesity, protein protein interaction, sex difference, waist hip ratio, Multidisciplinary Sciences, genetics [Transcription, Genetic], genetics [Polymorphism, Single Nucleotide], ADIPOGen Consortium, genetics [Neovascularization, Physiologic], Transcription, SUSCEPTIBILITY LOCI, General Science & Technology, ICBP, 030209 endocrinology & metabolism, Biology, adipocyte, MESH : Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism* Age Factors Body Fat Distribution* Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study* Humans Insulin/metabolism* Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics* Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio, MESENCHYMAL STEM-CELLS, GENIE Consortium, SEXUAL-DIMORPHISM, Insulin resistance, Internal medicine, medicine, genetics [Genome, Human], ABDOMINAL ADIPOSITY, Neovascularization, 030304 developmental biology, FALSE DISCOVERY, CKDGen Consortium, Sex Characteristic, MuTHER Consortium, numerical model
Abstract: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P
Published: 2015
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33. Biological interpretation of genome-wide association studies using predicted gene functions

Author: Pers TH, Karjalainen JM, Chan Y, Westra HJ, Wood AR, Yang J, Lui JC, Vedantam S, Gustafsson S, Esko T, Frayling T, Speliotes EK, Boehnke M, Raychaudhuri S, Fehrmann RS, Hirschhorn JN, Franke L, Chu AY, Estrada K, Luan J, Kutalik Z, Amin N, Buchkovich ML, Croteau Chonka DC, Day FR, Duan Y, Fall T, Fehrmann R, Ferreira T, Jackson AU, Karjalainen J, Lo KS, Locke AE, Mägi R, Mihailov E, Porcu E, Randall JC, Scherag A, Vinkhuyzen AA, Winkler TW, Workalemahu T, Zhao JH, Absher D, Albrecht E, Anderson D, Baron J, Beekman M, Demirkan A, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Fraser RM, Goel A, Gong J, Justice E, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Mangino M, Mateo Leach I, Medina Gomez C, Nalls MA, Nyholt DR, Palmer CD, Pasko D, Pechlivanis S, Prokopenko I, Ried JS, Ripke S, Shungin D, Stancáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Afzal U, Ärnlöv J, Arscott GM, Bandinelli S, Barrett A, Bellis C, Bennett AJ, Berne C, Blüher M, Bolton JL, Böttcher Y, Boyd HA, Bruinenberg M, Buckley BM, Buyske S, Caspersen IH, Chines PS, Clarke R, Claudi Boehm S, Cooper M, Daw EW, De Jong A, Deelen J, Delgado G, Denny JC, Dhonukshe Rutten R, Dimitriou M, Doney AS, Dörr M, Eklund N, Eury E, Folkersen L, Garcia ME, Geller F, Giedraitis V, Go AS, Grallert H, Grammer TB, Gräßler J, Grönberg H, de Groot LC, Groves CJ, Haessler J, Haller T, Hallmans G, Hannemann A, Hartman CA, Hassinen M, Hayward C, Heard Costa NL, Helmer Q, Hemani G, Henders AK, Hillege HL, Hlatky MA, Hoffmann W, Hoffmann P, Holmen O, Houwing Duistermaat JJ, Illig T, Isaacs A, James AL, Jeff J, Johansen B, Johansson Å, Jolley J, Juliusdottir T, Junttila J, Kho AN, Kinnunen L, Klopp N, Kocher T, Kratzer W, Lichtner P, Lind L, Lindström J, Lobbens S, Lorentzon M, Lu Y, Lyssenko V, Magnusson PK, Mahajan A, Maillard M, McArdle WL, McKenzie CA, McLachlan S, McLaren PJ, Menni C, Merger S, Milani L, Moayyeri A, Monda KL, Morken MA, Müller G, Müller Nurasyid M, Musk AW, Narisu N, Nauck M, Nolte IM, Nöthen MM, Oozageer L, Pilz S, Rayner NW, Renstrom F, Robertson NR, Rose LM, Roussel R, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Schunkert H, Scott RA, Sehmi J, Seufferlein T, Shi J, Silventoinen K, Smit JH, Smith AV, Smolonska J, Stanton AV, Stirrups K, Stott DJ, Stringham HM, Sundström J, Swertz MA, Syvänen AC, Tayo BO, Thorleifsson G, Tyrer JP, van Dijk S, van Schoor NM, van der Velde N, van Heemst D, van Oort FV, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Waldenberger M, Wennauer R, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q, Arveiler D, Bakker SJ, Beilby J, Bergman RN, Bergmann S, Biffar R, Blangero J, Boomsma I, Bornstein SR, Bovet P, BRAMBILLA, PAOLO, Brown MJ, Campbell H, Caulfield MJ, Chakravarti A, Collins R, Collins FS, Crawford DC, Cupples LA, Danesh J, de Faire U, den Ruijter HM, Erbel R, Erdmann J, Eriksson JG, Farrall M, Ferrannini E, Ferrières J, Ford I, Forouhi NG, Forrester T, Gansevoort RT, Gejman PV, Gieger C, Golay A, Gottesman O, Gudnason V, Gyllensten U, Haas DW, Hall AS, Harris TB, Hattersley AT, Heath AC, Hengstenberg C, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Hovingh GK, Humphries SE, Hunt SC, Hypponen E, Jacobs KB, Jarvelin MR, Jousilahti P, Jula AM, Kaprio J, Kastelein JJ, Kayser M, Kee F, Keinanen Kiukaanniemi SM, Kiemeney LA, Kooner JS, Kooperberg C, Koskinen S, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Le Marchand L, Lehtimäki T, Lupoli S, Madden PA, Männistö S, Manunta P, Marette A, Matise TC, McKnight B, Meitinger T, Moll FL, Montgomery GW, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Ouwehand WH, Pasterkamp G, Peters A, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ritchie M, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schwarz PE, Sebert S, Sever P, Shuldiner AR, Sinisalo J, Steinthorsdottir V, Stolk RP, Tardif JC, Tönjes A, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PI, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hayes MG, Hui J, Hunter DJ, Hveem K, Jukema JW, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, März W, Melbye M, Moebus S, Munroe PB, Njølstad I, Oostra BA, Palmer CN, Pedersen NL, Perola M, Pérusse L, Peters U, Powell JE, Power C, Quertermous T, Rauramaa R, Reinmaa E, Ridker PM, Rivadeneira F, Rotter JI, Saaristo TE, Saleheen D, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Strauch K, Stumvoll M, Tuomilehto J, Uusitupa M, van der Harst P, Völzke H, Walker M, Wareham NJ, Watkins H, Wichmann HE, Wilson JF, Zanen P, Deloukas P, Heid IM, Lindgren CM, Mohlke KL, Thorsteinsdottir U, Barroso I, Fox CS, North KE, Strachan DP, Beckmann JS, Berndt SI, Borecki IB, McCarthy MI, Metspalu A, Stefansson K, Uitterlinden AG, van Duijn CM, Willer CJ, Price AL, Lettre G, Loos RJ, Weedon MN, Ingelsson E, O'Connell JR, Abecasis GR, Chasman DI, Goddard ME, Visscher PM, Frayling T.M., Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Wood, AR., Esko, T., Yang, J., Vedantam, S., Pers, TH., Gustafsson, S., Chu, AY., Estrada, K., Luan£££Jian'an£££ J., Kutalik£££Zoltán£££ Z., Amin, N., Buchkovich, ML., Croteau-Chonka, DC., Day, FR., Duan, Y., Fall, T., Fehrmann, R., Ferreira, T., Jackson, AU., Karjalainen, J., Lo, KS., Locke, AE., Mägi, R., Mihailov, E., Porcu, E., Randall, JC., Scherag, A., Vinkhuyzen, AA., Westra, HJ., Winkler, TW., Workalemahu, T., Zhao, JH., Absher, D., Albrecht, E., Anderson, D., Baron, J., Beekman, M., Demirkan, A., Ehret, GB., Feenstra, B., Feitosa, MF., Fischer, K., Fraser, RM., Goel, A., Gong, J., Justice, E., Kanoni, S., Kleber, ME., Kristiansson, K., Lim, U., Lotay, V., Lui, JC., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Nalls, MA., Nyholt, DR., Palmer, CD., Pasko, D., Pechlivanis, S., Prokopenko, I., Ried, JS., Ripke, S., Shungin, D., Stancáková, A., Strawbridge, RJ., Sung, YJ., Tanaka, T., Teumer, A., Trompet, S., van der Laan SW., van Setten, J., Van Vliet-Ostaptchouk JV., Wang, Z., Yengo£££Loïc£££ L., Zhang, W., Afzal, U., Ärnlöv, J., Arscott, GM., Bandinelli, S., Barrett, A., Bellis, C., Bennett, AJ., Berne, C., Blüher, M., Bolton, JL., Böttcher, Y., Boyd, HA., Bruinenberg, M., Buckley, BM., Buyske, S., Caspersen, IH., Chines, PS., Clarke, R., Claudi-Boehm, S., Cooper, M., Daw, EW., De Jong, A., Deelen, J., Delgado, G., Denny, JC., Dhonukshe-Rutten, R., Dimitriou, M., Doney, AS., Dörr, M., Eklund, N., Eury, E., Folkersen, L., Garcia, ME., Geller, F., Giedraitis, V., Go, AS., Grallert, H., Grammer, TB., Gräßler, J., Grönberg, H., de Groot LC., Groves, CJ., Haessler, J., Haller, T., Hallmans, G., Hannemann, A., Hartman, CA., Hassinen, M., Hayward, C., Heard-Costa, NL., Helmer, Q., Hemani, G., Henders, AK., Hillege, HL., Hlatky, MA., Hoffmann, W., Hoffmann, P., Holmen, O., Houwing-Duistermaat, JJ., Illig, T., Isaacs, A., James, AL., Jeff, J., Johansen, B., Johansson£££Åsa£££ Å., Jolley, J., Juliusdottir, T., Junttila, J., Kho, AN., Kinnunen, L., Klopp, N., Kocher, T., Kratzer, W., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Lu, Y., Lyssenko, V., Magnusson, PK., Mahajan, A., Maillard, M., McArdle, WL., McKenzie, CA., McLachlan, S., McLaren, PJ., Menni, C., Merger, S., Milani, L., Moayyeri, A., Monda, KL., Morken, MA., Müller, G., Müller-Nurasyid, M., Musk, AW., Narisu, N., Nauck, M., Nolte, IM., Nöthen, MM., Oozageer, L., Pilz, S., Rayner, NW., Renstrom, F., Robertson, NR., Rose, LM., Roussel, R., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, FR., Schunkert, H., Scott, RA., Sehmi, J., Seufferlein, T., Shi, J., Silventoinen, K., Smit, JH., Smith, AV., Smolonska, J., Stanton, AV., Stirrups, K., Stott, DJ., Stringham, HM., Sundström, J., Swertz, MA., Syvänen, AC., Tayo, BO., Thorleifsson, G., Tyrer, JP., van Dijk, S., van Schoor NM., van der Velde, N., van Heemst, D., van Oort FV., Vermeulen, SH., Verweij, N., Vonk, JM., Waite, LL., Waldenberger, M., Wennauer, R., Wilkens, LR., Willenborg, C., Wilsgaard, T., Wojczynski, MK., Wong, A., Wright, AF., Zhang, Q., Arveiler, D., Bakker, SJ., Beilby, J., Bergman, RN., Bergmann, S., Biffar, R., Blangero, J., Boomsma, I., Bornstein, SR., Bovet, P., Brambilla, P., Brown, MJ., Campbell, H., Caulfield, MJ., Chakravarti, A., Collins, R., Collins, FS., Crawford, DC., Cupples, LA., Danesh, J., de Faire, U., den Ruijter HM., Erbel, R., Erdmann, J., Eriksson, JG., Farrall, M., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, NG., Forrester, T., Gansevoort, RT., Gejman, PV., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, DW., Hall, AS., Harris, TB., Hattersley, AT., Heath, AC., Hengstenberg, C., Hicks, AA., Hindorff, LA., Hingorani, AD., Hofman, A., Hovingh, GK., Humphries, SE., Hunt, SC., Hypponen, E., Jacobs, KB., Jarvelin, MR., Jousilahti, P., Jula, AM., Kaprio, J., Kastelein, JJ., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, SM., Kiemeney, LA., Kooner, JS., Kooperberg, C., Koskinen, S., Kovacs, P., Kraja, AT., Kumari, M., Kuusisto, J., Lakka, TA., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lupoli, S., Madden, PA., Männistö, S., Manunta, P., Marette, A., Matise, TC., McKnight, B., Meitinger, T., Moll, FL., Montgomery, GW., Morris, AD., Morris, AP., Murray, JC., Nelis, M., Ohlsson, C., Oldehinkel, AJ., Ong, KK., Ouwehand, WH., Pasterkamp, G., Peters, A., Pramstaller, PP., Price, JF., Qi, L., Raitakari, OT., Rankinen, T., Rao, DC., Rice, TK., Ritchie, M., Rudan, I., Salomaa, V., Samani, NJ., Saramies, J., Sarzynski, MA., Schwarz, PE., Sebert, S., Sever, P., Shuldiner, AR., Sinisalo, J., Steinthorsdottir, V., Stolk, RP., Tardif, JC., Tönjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, MC., Amouyel, P., Asselbergs, FW., Assimes, TL., Bochud, M., Boehm, BO., Boerwinkle, E., Bottinger, EP., Bouchard, C., Cauchi, S., Chambers, JC., Chanock, SJ., Cooper, RS., de Bakker PI., Dedoussis, G., Ferrucci, L., Franks, PW., Froguel, P., Groop, LC., Haiman, CA., Hamsten, A., Hayes, MG., Hui, J., Hunter, DJ., Hveem, K., Jukema, JW., Kaplan, RC., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, NG., März, W., Melbye, M., Moebus, S., Munroe, PB., Njølstad, I., Oostra, BA., Palmer, CN., Pedersen, NL., Perola, M., Pérusse, L., Peters, U., Powell, JE., Power, C., Quertermous, T., Rauramaa, R., Reinmaa, E., Ridker, PM., Rivadeneira, F., Rotter, JI., Saaristo, TE., Saleheen, D., Schlessinger, D., Slagboom, PE., Snieder, H., Spector, TD., Strauch, K., Stumvoll, M., Tuomilehto, J., Uusitupa, M., van der Harst, P., Völzke, H., Walker, M., Wareham, NJ., Watkins, H., Wichmann, HE., Wilson, JF., Zanen, P., Deloukas, P., Heid, IM., Lindgren, CM., Mohlke, KL., Speliotes, EK., Thorsteinsdottir, U., Barroso£££Inês£££ I., Fox, CS., North, KE., Strachan, DP., Beckmann, JS., Berndt, SI., Boehnke, M., Borecki, IB., McCarthy, MI., Metspalu, A., Stefansson, K., Uitterlinden, AG., van Duijn CM., Franke, L., Willer, CJ., Price, AL., Lettre, G., Loos, RJ., Weedon, MN., Ingelsson, E., O'Connell, JR., Abecasis, GR., Chasman, DI., Goddard, ME., Visscher, PM., Hirschhorn, JN., Frayling, TM., Clinicum, Jaakko Kaprio / Principal Investigator, Department of Public Health, Institute for Molecular Medicine Finland, Genetic Epidemiology, Pers, T, Karjalainen, J, Chan, Y, Westra, H, Wood, A, Yang, J, Lui, J, Vedantam, S, Gustafsson, S, Esko, T, Frayling, T, Speliotes, E, Boehnke, M, Raychaudhuri, S, Fehrmann, R, Hirschhorn, J, Franke, L, Chu, A, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, M, Croteau Chonka, D, Day, F, Duan, Y, Fall, T, Ferreira, T, Jackson, A, Lo, K, Locke, A, Mägi, R, Mihailov, E, Porcu, E, Randall, J, Scherag, A, Vinkhuyzen, A, Winkler, T, Workalemahu, T, Zhao, J, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Fraser, R, Goel, A, Gong, J, Justice, E, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, M, Nyholt, D, Palmer, C, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, J, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, van der Laan, S, van Setten, J, Van Vliet Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Bolton, J, Böttcher, Y, Boyd, H, Bruinenberg, M, Buckley, B, Buyske, S, Caspersen, I, Chines, P, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, E, De Jong, A, Deelen, J, Delgado, G, Denny, J, Dhonukshe Rutten, R, Dimitriou, M, Doney, A, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, M, Geller, F, Giedraitis, V, Go, A, Grallert, H, Grammer, T, Gräßler, J, Grönberg, H, de Groot, L, Groves, C, Haessler, J, Haller, T, Hallmans, G, Hannemann, A, Hartman, C, Hassinen, M, Hayward, C, Heard Costa, N, Helmer, Q, Hemani, G, Henders, A, Hillege, H, Hlatky, M, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat, J, Illig, T, Isaacs, A, James, A, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, A, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, P, Mahajan, A, Maillard, M, Mcardle, W, Mckenzie, C, Mclachlan, S, Mclaren, P, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, K, Morken, M, Müller, G, Müller Nurasyid, M, Musk, A, Narisu, N, Nauck, M, Nolte, I, Nöthen, M, Oozageer, L, Pilz, S, Rayner, N, Renstrom, F, Robertson, N, Rose, L, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Schunkert, H, Scott, R, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, J, Smith, A, Smolonska, J, Stanton, A, Stirrups, K, Stott, D, Stringham, H, Sundström, J, Swertz, M, Syvänen, A, Tayo, B, Thorleifsson, G, Tyrer, J, van Dijk, S, van Schoor, N, van der Velde, N, van Heemst, D, van Oort, F, Vermeulen, S, Verweij, N, Vonk, J, Waite, L, Waldenberger, M, Wennauer, R, Wilkens, L, Willenborg, C, Wilsgaard, T, Wojczynski, M, Wong, A, Wright, A, Zhang, Q, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Bergmann, S, Biffar, R, Blangero, J, Boomsma, I, Bornstein, S, Bovet, P, Brambilla, P, Brown, M, Campbell, H, Caulfield, M, Chakravarti, A, Collins, R, Collins, F, Crawford, D, Cupples, L, Danesh, J, de Faire, U, den Ruijter, H, Erbel, R, Erdmann, J, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Ford, I, Forouhi, N, Forrester, T, Gansevoort, R, Gejman, P, Gieger, C, Golay, A, Gottesman, O, Gudnason, V, Gyllensten, U, Haas, D, Hall, A, Harris, T, Hattersley, A, Heath, A, Hengstenberg, C, Hicks, A, Hindorff, L, Hingorani, A, Hofman, A, Hovingh, G, Humphries, S, Hunt, S, Hypponen, E, Jacobs, K, Jarvelin, M, Jousilahti, P, Jula, A, Kaprio, J, Kastelein, J, Kayser, M, Kee, F, Keinanen Kiukaanniemi, S, Kiemeney, L, Kooner, J, Kooperberg, C, Koskinen, S, Kovacs, P, Kraja, A, Kumari, M, Kuusisto, J, Lakka, T, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lupoli, S, Madden, P, Männistö, S, Manunta, P, Marette, A, Matise, T, Mcknight, B, Meitinger, T, Moll, F, Montgomery, G, Morris, A, Murray, J, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Ouwehand, W, Pasterkamp, G, Peters, A, Pramstaller, P, Price, J, Qi, L, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schwarz, P, Sebert, S, Sever, P, Shuldiner, A, Sinisalo, J, Steinthorsdottir, V, Stolk, R, Tardif, J, Tönjes, A, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, M, Amouyel, P, Asselbergs, F, Assimes, T, Bochud, M, Boehm, B, Boerwinkle, E, Bottinger, E, Bouchard, C, Cauchi, S, Chambers, J, Chanock, S, Cooper, R, de Bakker, P, Dedoussis, G, Ferrucci, L, Franks, P, Froguel, P, Groop, L, Haiman, C, Hamsten, A, Hayes, M, Hui, J, Hunter, D, Hveem, K, Jukema, J, Kaplan, R, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, Martin, N, März, W, Melbye, M, Moebus, S, Munroe, P, Njølstad, I, Oostra, B, Pedersen, N, Perola, M, Pérusse, L, Peters, U, Powell, J, Power, C, Quertermous, T, Rauramaa, R, Reinmaa, E, Ridker, P, Rivadeneira, F, Rotter, J, Saaristo, T, Saleheen, D, Schlessinger, D, Slagboom, P, Snieder, H, Spector, T, Strauch, K, Stumvoll, M, Tuomilehto, J, Uusitupa, M, van der Harst, P, Völzke, H, Walker, M, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Zanen, P, Deloukas, P, Heid, I, Lindgren, C, Mohlke, K, Thorsteinsdottir, U, Barroso, I, Fox, C, North, K, Strachan, D, Beckmann, J, Berndt, S, Borecki, I, Mccarthy, M, Metspalu, A, Stefansson, K, Uitterlinden, A, van Duijn, C, Willer, C, Price, A, Lettre, G, Loos, R, Weedon, M, Ingelsson, E, O'Connell, J, Abecasis, G, Chasman, D, Goddard, M, Visscher, P, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Pers, Th, Karjalainen, Jm, Westra, Hj, Wood, Ar, Lui, Jc, Speliotes, Ek, Hirschhorn, Jn, and Faculty of Health Sciences
Subjects: Cell type, Candidate gene, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, LOCI, General Physics and Astronomy, Genome-wide association study, Disease, Computational biology, Biology, Research Support, General Biochemistry, Genetics and Molecular Biology, Article, DISEASE, N.I.H, CANDIDATE GENES, Genome-Wide Association Study/methods, Software, HEIGHT, Research Support, N.I.H., Extramural, Genetics, Journal Article, NETWORK, Non-U.S. Gov't, Gene, COMMON, Intramural, ARCHITECTURE, Biochemistry, Genetics and Molecular Biology (all), Multidisciplinary, IDENTIFICATION, ta1184, Research Support, Non-U.S. Gov't, Gene sets, Extramural, General Chemistry, ta3121, Research Support, N.I.H., Intramural, Phenotype, 3142 Public health care science, environmental and occupational health, Biological sciences, DATA SETS, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Identification (biology), INTEGRATION, Genome-Wide Association Study
Abstract: Article, The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes., published version, http://purl.org/eprint/status/PeerReviewed
Published: 2015
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34. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Author: Xue, A., Wu, Y., Zhu, Z., Zhang, F., Kemper, K.E., Zheng, Z., Yengo, L., Lloyd-Jones, L.R., Sidorenko, J., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Beutner, F., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Favé, M.-J., Franke, L., Frayling, T., Gharib, S., Gibson, G., Hemani, G., Jansen, R., Kähönen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U.M., Metspalu, A., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., van Dongen, J., van Meurs, J., Verlouw, J., Völker, U., Võsa, U., Yaghootkar, H., Zeng, B., McRae, A.F., Visscher, P.M., Zeng, J., Yang, J., Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Clinicum, Complex Disease Genetics, Psychiatry, APH - Digital Health, and Internal Medicine
Subjects: 0301 basic medicine, Epigenomics, Netherlands Twin Register (NTR), endocrine system diseases, General Physics and Astronomy, Genome-wide association study, Epigenesis, Genetic, Genotype, lcsh:Science, Heat-Shock Proteins, Genetics, Multidisciplinary, Mitochondrial Proton-Translocating ATPases, 3. Good health, DNA methylation, Risk, endocrine system, Science, education, Biology, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Humans, Genetic Predisposition to Disease, Epigenetics, Gene, Genetic association, Genetic Variation, nutritional and metabolic diseases, General Chemistry, DNA Methylation, 030104 developmental biology, Calcium-Calmodulin-Dependent Protein Kinase Type 1, Diabetes Mellitus, Type 2, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, lcsh:Q, 3111 Biomedicine, Carrier Proteins, human activities, Genome-Wide Association Study
Abstract: Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants., GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.
Published: 2018
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35. ATG7-expression and chemerin secretion are co-regulated in adipocytes

Author: Assaf Rudich, Paolo Piaggi, A Tönjes, Peter Kovacs, Henrike O. Heyne, S Heinitz, Michael Stumvoll, Claudia Gebhardt, Matthias Blüher, J Krüger, Juliane Weiner, Leslie J. Baier, and John T. Heiker
Subjects: biology, Chemistry, biology.protein, Chemerin, Secretion, Cell biology
Published: 2018
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36. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Author: Ching-Ti Liu, Michael Boehnke, George Dedoussis, Sophie V. Eastwood, Ruth J. F. Loos, Keng-Hung Lin, Denis Rybin, Fredrik Karpe, Martina Müller-Nurasyid, Michael A. Province, Alison D. Murray, Bo Isomaa, Eirini Marouli, Konstantin Strauch, Michael Preuss, Paul M. Ridker, Jette Bork-Jensen, Albert V. Smith, Hugoline G. de Haan, Wayne Huey-Herng Sheu, Barbara Thorand, Wolfgang Rathmann, Lawrence F. Bielak, Peter Kovacs, Marit E. Jørgensen, Jennifer Wessel, Danish Saleheen, Jung-Jin Lee, James B. Meigs, Veikko Salomaa, Alena Stančáková, Tibor V. Varga, Hidetoshi Kitajima, Inês Barroso, Kent D. Taylor, Claudia Langenberg, Yoon Shin Cho, Joanna M. M. Howson, Andrew T. Hattersley, Marie-France Hivert, Markku Laakso, Kai-Uwe Eckardt, Bram P. Prins, Matthias B. Schulze, Andrew D. Morris, Susanne Jäger, Francis S. Collins, Kristi Läll, Xu Lin, Anette Varbo, Benjamin Lehne, Girish N. Nadkarni, Jonathan Marchini, Daniel I. Chasman, Michael Stumvoll, Mark O. Goodarzi, Cécile Lecoeur, Philippe M. Frossard, Noël P. Burtt, Frank Kee, Jasmina Kravic, Alain G. Bertoni, Ivan Brandslund, Najaf Amin, Lenore J. Launer, Oluf Pedersen, Johanna Kuusisto, Line Rode, Eleftheria Zeggini, Yingchang Lu, Markus Perola, Helen R. Warren, André G. Uitterlinden, Hanieh Yaghootkar, Torben Hansen, Harald Grallert, Annemari Käräjämäki, Abbas Dehghan, Gina M. Peloso, Yii-Der Ida Chen, Man Li, Shaofeng Huo, Lars Lind, Karen L. Mohlke, Adrienne Tin, Yang Hai, Renée de Mutsert, Gudmar Thorleifsson, Marie Moitry, Sune F. Nielsen, Sara M. Willems, Matthias Wuttke, Weihua Zhang, Young-Jin Kim, Giovanni Malerba, Richard A. Jensen, Loic Yengo, Mickaël Canouil, Kurt Lohman, Robert A. Scott, Tamara B. Harris, Ruifang Li-Gao, Florian Kronenberg, Anke Tönjes, Bok-Ghee Han, Krista Fischer, Thomas Meitinger, James S. Pankow, Jaakko Tuomilehto, Adam S. Butterworth, Jerome I. Rotter, Olov Rolandsson, Xiuqing Guo, Cramer Christensen, Marie Loh, Elizabeth Selvin, Bong-Jo Kim, Audrey Y. Chu, Reedik Mägi, Josée Dupuis, Anna Köttgen, Jean Ferrières, Jin Li, Robert Sladek, Leslie A. Lange, Niels Grarup, Roberta McKean-Cowdin, Cristen J. Willer, Jose C. Florez, Valgerdur Steinthorsdottir, Karina Meidtner, Annette Peters, Børge G. Nordestgaard, Rajiv Chowdhury, Ioanna Ntalla, Emma Ahlqvist, Leif Groop, Nicholas J. Wareham, Kerrin S. Small, Tiinamaija Tuomi, Cecilia M. Lindgren, Katharine R. Owen, Giovanni Gambaro, Cornelia M. van Duijn, Dennis O. Mook-Kanamori, Kenneth Rice, Erik Ingelsson, Colin N. A. Palmer, Sharon L.R. Kardia, Neil R. Robertson, Dajiang J. Liu, Sebastian Schönherr, Daniel Taliun, Sekar Kathiresan, James G. Wilson, Ping An, Patricia A. Peyser, Matthias Blüher, Frits R. Rosendaal, John C. Chambers, Caroline Hayward, Shoaib Afzal, Fernando Rivadineira, Marielisa Graff, Pranav Yajnik, Vasiliki Mamakou, Juan Fernandez Tajes, Stefan Gustafsson, Heather M. Highland, Vilmantas Giedraitis, Andrew R. Wood, Saima Afaq, Jaspal S. Kooner, Megan L. Grove, Jennifer A. Brody, Andrew P. Morris, James P. Cook, Praveen Surendran, Jennifer Kriebel, Heikki A. Koistinen, Kari Stefansson, Anders Rosengren, Rainer Rauramaa, Satu Männistö, Oscar H. Franco, Yongmei Liu, N. William Rayner, Blair H. Smith, Erwin P. Bottinger, Ayse Demirkan, Allan Linneberg, Jonathan Marten, Huaixing Li, Sung Soo Kim, Sophie Hackinger, Cristina Bombieri, Lia B. Bang, Jun Liu, Asif Rasheed, Tim D. Spector, Paul W. Franks, Mark I. McCarthy, Heiner Boeing, Anne E. Justice, Vilmundur Gudnason, Sohee Han, Unnur Thorsteinsdottir, Panos Deloukas, Naveed Sattar, Eric Boerwinkle, Martin Ingelsson, John Danesh, Vassily Trubetskoy, Marco M Ferrario, Marju Orho-Melander, Wei Gan, Philippe Froguel, Symen Ligthart, Susan R. Heckbert, Jie Yao, Anne Tybjærg-Hansen, Robin Young, Daniel R. Witte, Anubha Mahajan, Peter Almgren, Timothy M. Frayling, Tanya M. Teslovich, Matt Neville, Philippe Amouyel, Wei Zhao, Andres Metspalu, Yao Hu, Olle Melander, Kari Kuulasmaa, Jason Flannick, Torben Jørgensen, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Rohit Varma, Epidemiology, and Internal Medicine
Subjects: 0301 basic medicine, Male, Inference, Genome-wide association study, Whole Exome Sequencing, 0302 clinical medicine, type 2 diabetes, coding variant associations signals, mechanistic inference, fine mapping, Coding region, Chromosome Mapping/statistics & numerical data, European Continental Ancestry Group/genetics, CONFERS SUSCEPTIBILITY, Exome sequencing, 11 Medical and Health Sciences, Genetics, Genetics & Heredity, 0303 health sciences, MAGIC Consortium, Chromosome Mapping, Whole Exome Sequencing/statistics & numerical data, Identification (information), RARE VARIANTS, LOW-FREQUENCY, Female, ExomeBP Consortium, Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, Posterior probability, European Continental Ancestry Group, 030209 endocrinology & metabolism, Context (language use), Computational biology, Biology, GENOTYPE IMPUTATION, Article, White People, GENETIC ARCHITECTURE, 03 medical and health sciences, SDG 3 - Good Health and Well-being, QUALITY-CONTROL, Exome Sequencing, Genome-Wide Association Study/statistics & numerical data, Journal Article, GIANT Consortium, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Alleles, Genetic association, 030304 developmental biology, FATTY LIVER-DISEASE, Science & Technology, Genetic Variation, 06 Biological Sciences, Genetic architecture, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 2/classification, 030217 neurology & neurosurgery, Coding (social sciences), Genome-Wide Association Study, Developmental Biology
Abstract: Identification of coding variant associations for complex diseases offers a direct route to biological insight, but is dependent on appropriate inference concerning the causal impact of those variants on disease risk. We aggregated coding variant data for 81,412 type 2 diabetes (T2D) cases and 370,832 controls of diverse ancestry, identifying 40 distinct coding variant association signals (at 38 loci) reaching significance (p−7). Of these, 16 represent novel associations mapping outside known genome-wide association study (GWAS) signals. We make two important observations. First, despite a threefold increase in sample size over previous efforts, only five of the 40 signals are driven by variants with minor allele frequency 1.29. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls of European ancestry to fine-map these associated coding variants in their regional context, with and without additional weighting to account for the global enrichment of complex trait association signals in coding exons. At the 37 signals for which we attempted fine-mapping, we demonstrate convincing support (posterior probability >80% under the “annotation-weighted” model) that coding variants are causal for the association at 16 (including novel signals involving POC5 p.His36Arg, ANKH p.Arg187Gln, WSCD2 p.Thr113Ile, PLCB3 p.Ser778Leu, and PNPLA3 p.Ile148Met). However, at 13 of the 37 loci, the associated coding variants represent “false leads” and naïve analysis could have led to an erroneous inference regarding the effector transcript mediating the signal. Accurate identification of validated targets is dependent on correct specification of the contribution of coding and non-coding mediated mechanisms at associated loci.
Published: 2018
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37. Comparative gene expression profiling of pig-derived iPSC-like cells: Effects of induced pluripotency on expression of porcine endogenous retrovirus (PERV)

Author: Barbara Gulich, Nicole Fischer, Antonia W. Godehardt, Heiner Niemann, Stoyan Petkov, and Ralf R. Tönjes
Subjects: 0301 basic medicine, Swine, Immunology, Induced Pluripotent Stem Cells, Transplantation, Heterologous, Endogenous retrovirus, Gene Expression, 030230 surgery, 03 medical and health sciences, 0302 clinical medicine, Retrovirus, Gene expression, Animals, Humans, Induced pluripotent stem cell, Cells, Cultured, Transplantation, biology, Endogenous Retroviruses, biology.organism_classification, Reverse transcriptase, Cell biology, Gene expression profiling, 030104 developmental biology, Stem cell, Reprogramming
Abstract: Background Porcine induced pluripotent stem cells (piPSCs) offer an alternative strategy in xenotransplantation (XTx). As human endogenous retroviruses (HERV), particularly HERV‐K, are highly expressed in natural human stem cells, we compared the expression of porcine endogenous retroviruses (PERV) and retrotransposon LINE‐1 (L1) open reading frames 1 and 2 (pORF1 and pORF2) in different piPSC‐like cell lines with their progenitors (porcine fetal fibroblasts, pFF). Methods Cells reprogrammed via Sleeping Beauty‐transposed transcription factors were cultured and analyzed on a custom‐designed microarray representing the reference pig genome. Data were complemented by qRT‐PCR and reverse transcriptase (RT) assay. Results The expression profiles revealed that 8515 of 26 967 targets were differentially expressed. A total of 4443 targets showed log2 expression ratio >1, and 4072 targets showed log2 expression ratio less than −1 with 0.05 P‐value threshold. Approximately ten percent of the targets showed highly significant expression ratios with log2 ≥4 or ≤−4. Besides this general switch in cellular gene expression that was accompanied by an altered morphology, expression of both PERV and L1 pORF1/pORF2 was significantly enhanced. piPSC‐like cells revealed a 10‐fold to 100‐fold higher transcription of the viral PERV‐A and PERV‐B envelope genes (env), viral protease/polymerase (prt/pol), and L1 elements. No functional retrovirus could be detected under these conditions. Conclusion Epigenetic reprogramming has functional impact on retrotransposons. Thus, the induction of pig‐derived pluripotent cells influences their PERV expression profile. Data emphasize the necessity to focus on animals, which show non‐functional endogenous viral background to ensure virological safety.
Published: 2018

38. Metabolic effects of genetic variation in the human REPIN1 gene

Author: Peter Kovacs, Anke Tönjes, Nora Klöting, Dorit Schleinitz, Michael Stumvoll, Claudia Berger, Kerstin Weidle, Matthias Blüher, and Jacqueline Krüger
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Quantitative Trait Loci, Medicine (miscellaneous), Adipose tissue, 030209 endocrinology & metabolism, Quantitative trait locus, Carbohydrate metabolism, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Lipid droplet, Germany, medicine, Humans, 030212 general & internal medicine, Cells, Cultured, chemistry.chemical_classification, Nutrition and Dietetics, biology, Triglyceride, Fatty acid, Genetic Variation, RNA-Binding Proteins, Lipid metabolism, Lipid Metabolism, DNA-Binding Proteins, Endocrinology, Glucose, chemistry, Gene Expression Regulation, biology.protein, GLUT2, Insulin Resistance
Abstract: Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue. The Repin1 resides within a quantitative trait locus (QTL) for body weight and triglyceride levels in the rat, and its hepatic deletion in mice results in improved insulin sensitivity and lower body weight. Here, we analyzed whether genetic variation within the Repin1 affects parameters of glucose and lipid metabolism. We sequenced REPIN1 in 48 non-related Caucasian subjects. We discovered a 12 base pair deletion (12 bp del; rs3832490), which was subsequently genotyped in two well-characterized cohorts (N = 3013) to test for associations with metabolic traits. Functional consequences of the variant were investigated in HepG2 cells in vitro. In human cohorts, we show that the 12 bp del associates with improved glucose metabolism (lower fasting plasma glucose, fasting plasma insulin, and HOMA IR). Cells transfected with the plasmid carrying the 12 bp del variant are characterized by increased GLUT2 and fatty acid translocase CD36 expression and more lipid droplets. Our data suggest that genetic variation in human REPIN1 plays a role in glucose and lipid metabolism by differentially affecting the expression of REPIN1 target genes including glucose and fatty acid transporters.
Published: 2018

39. Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin

Author: Wolfgang Rathmann, Knut Krohn, Antje Fischer-Rosinsky, Peter Kovacs, Joachim Spranger, Jürgen Kratzsch, Christian Gieger, Frank Beutner, Bo Isomaa, Carola Marzi, Jennifer Kriebel, Christa Meisinger, Claes Ladenvall, Claudia Gebhardt, Anke Tönjes, Henrike O. Heyne, Andreas Pfeiffer, Dorit Schleinitz, Leif Groop, Jacqueline Krüger, Michael Stumvoll, Joachim Thiery, Inga Prokopenko, Matthias Blüher, Kerstin Krause, Markus Scholz, Esa Laurila, Harald Grallert, and Holger Kirsten
Subjects: EXPRESSION, 0301 basic medicine, Biochemistry & Molecular Biology, GROWTH-FACTOR, Genotype, LOCI, Single-nucleotide polymorphism, Genome-wide association study, 030105 genetics & heredity, Quantitative trait locus, Biology, Peripheral blood mononuclear cell, Polymorphism, Single Nucleotide, 03 medical and health sciences, Mice, Progranulins, mental disorders, Genetics, Animals, Humans, RNA, Messenger, Molecular Biology, Gene, Genetics (clinical), Genetic association, Genetics & Heredity, FRONTOTEMPORAL LOBAR DEGENERATION, INSULIN-RESISTANCE, Gene knockdown, Science & Technology, PLASMA, TRANS-EQTLS, DDA3, 11 Medical And Health Sciences, General Medicine, 06 Biological Sciences, Phosphoproteins, ASSOCIATION ANALYSIS, ADIPOSE-TISSUE, 030104 developmental biology, Leukocytes, Mononuclear, Life Sciences & Biomedicine, Genome-Wide Association Study
Abstract: © The Author(s) 2017. Published by Oxford University Press. All rights reserved. Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N=848) and KORA (N=1628) from Germany and PPP-Botnia (N=335) from Finland (total N=2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N=967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N=833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR 2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23- PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P=5.75x10 -50 ), which was also associated with mRNA expression of PSRC1 in PBMC (P=1.51x10 -21 ). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.
Published: 2018

40. The Effects of Thyroid Hormones on Gene Expression of Acyl-Coenzyme A Thioesterases in Adipose Tissue and Liver of Mice

Author: Juliane Weiner, Lars C. Moeller, Nora Klöting, S Hönes, John T. Heiker, Karen Steinhoff, Claudia Gebhardt, Josef Köhrle, Eddy Rijntjes, Dagmar Führer, Kerstin Krause, Swen Hesse, and Anke Tönjes
Subjects: Translational Thyroidology / Original Paper, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Medizin, Adipose tissue, White adipose tissue, Biology, Lipid storage, Acyl coenzyme A, Endocrinology, medicine.anatomical_structure, Biochemistry, Thyroid hormones, Internal medicine, Gene expression, Brown adipose tissue, medicine, lipids (amino acids, peptides, and proteins), Cholesterol homeostasis
Abstract: Thyroid hormones (TH) exert pleiotropic effects on glucose and lipid homeostasis. However, it is as yet unclear how TH regulate lipid storage and utilization in order to adapt to metabolic needs. Acyl-CoA thioesterases (ACOTs) have been proposed to play a regulatory role in the metabolism of fatty acids.We investigated the interaction between thyroid dysfunction and Acot expression in adipose tissues and livers of thyrotoxic and hypothyroid mice.Ten-week-old female C57BL/6NTac mice (n = 10/group) were made hyperthyroid by the application of L-thyroxine (2 µg/ml in drinking water) for 4 weeks. Hypothyroidism was induced in 10-week-old mice by feeding an iodine-free chow supplemented with 0.15% PTU for 4 weeks. We measured mRNA expression levels of Acot8, 11 and 13 in the liver and epididymal and inguinal white and brown adipose tissues (BAT). Furthermore, we investigated hepatic Acot gene expression in TRα- and TRβ-deficient mice.We showed that the expression of Acot8, 11 and 13 is predominantly stimulated by a thyrotoxic state in the epididymal white adipose tissue. In contrast, hypothyroidism predominantly induces the expression of Acot8 in BAT in comparison with BAT of thyrotoxic and euthyroid mice (p0.01). However, no significant changes in Acot expression were observed in inguinal white adipose tissue. In liver, Acot gene expression is collectively elicited by a thyrotoxic state.These data suggest that ACOTs are targets of TH and are likely to influence 3,5,3'-triiodo-L-thyronine-orchestrated mechanisms of lipid uptake, storage and utilization to adapt the regulation of metabolic demands.
Published: 2015
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41. Review on porcine endogenous retrovirus detection assays—impact on quality and safety of xenotransplants

Author: Antonia W. Godehardt, Michael Rodrigues Costa, and Ralf R. Tönjes
Subjects: Xenotransplantation, medicine.medical_treatment, media_common.quotation_subject, Immunology, Sus scrofa, Transplantation, Heterologous, Endogenous retrovirus, Biology, Cell therapy, chemistry.chemical_compound, Risk Factors, xenotransplantation, medicine, Animals, Humans, Quality (business), RNA-Seq, porcine endogenous retrovirus, Review Articles, media_common, Transplantation, Porcine endogenous retrovirus, Sequence Analysis, RNA, Gene Expression Profiling, Endogenous Retroviruses, cocultivation, Virology, Coculture Techniques, Gene expression profiling, chemistry, microarray analysis, ATMP, Retroviridae Infections
Abstract: Xenotransplantation of porcine organs, tissues, and cells inherits a risk for xenozoonotic infections. Viable tissues and cells intended for transplantation have to be considered as potentially contaminated non-sterile products. The demands on microbial testing, based on the regulatory requirements, are often challenging due to a restricted shelf life or the complexity of the product itself. In Europe, the regulatory framework for xenogeneic cell therapy is based on the advanced therapy medicinal products (ATMP) regulation (2007), the EMA CHMP Guideline on xenogeneic cell-based medicinal products (2009), as well as the WHO and Council of Europe recommendations. In the USA, FDA guidance for industry (2003) regulates the use of xenotransplants. To comply with the regulations, validated test methods need to be established that reveal the microbial status of a transplant within its given shelf life, complemented by strictly defined action alert limits and supported by breeding in specific pathogen-free (SPF) facilities. In this review, we focus on assays for the detection of the porcine endogenous retroviruses PERV-A/-B/-C, which exhibit highly polymorphic proviral loci in pig genomes. PERVs are transmitted vertically and cannot be completely eliminated by breeding or gene knock out technology. PERVs entail a public health concern that will persist even if no evidence of PERV infection of xenotransplant recipients in vivo has been revealed yet. Nevertheless, infectious risks must be minimized by full assessment of pigs as donors by combining different molecular screening assays for sensitive and specific detection as well as a functional analysis of the infectivity of PERV including an adequate monitoring of recipients.
Published: 2015

42. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

Author: Consortium, Coffee and Caffeine Genetics, Cornelis, Marilyn C, Renstrom, Frida, Rasheed, Asif, Mason, Marc A, Zonderman, Alan B, Franke, Lude, Kristal, Bruce S, Consortium, International Parkinson’s Disease Genomics, Consortium, North American Brain Expression, Consortium, UK Brain Expression, Karjalainen, Juha, Reed, Danielle R, Ngwa, Julius S, Westra, Harm-Jan, Evans, Michele K, Saleheen, Danish, Harris, Tamara B, Dedoussis, George, Curhan, Gary, Stumvoll, Michael, Beilby, John, Pasquale, Louis R, Feenstra, Bjarke, Huikari, Ville, Bandinelli, Stefania, Ordovas, Jose M, Chan, Andrew T, Peters, Ulrike, Ohlsson, Claes, Gieger, Christian, Martin, Nicholas G, Waldenberger, Melanie, Siscovick, David S, Raitakari, Olli, Cavadino, Alana, Eriksson, Johan G, Mitchell, Paul, Hunter, David J, Kraft, Peter, Rimm, Eric B, Boomsma, Dorret I, Borecki, Ingrid B, Loos, Ruth Jf, Wareham, Nicholas J, Vollenweider, Peter, Nolte, Ilja M, Caporaso, Neil, Grabe, Hans Jörgen, Neuhouser, Marian L, Wolffenbuttel, Bruce Hr, Hu, Frank B, Hyppönen, Elina, Järvelin, Marjo-Riitta, Cupples, L Adrienne, Franks, Paul W, Ridker, Paul M, Teumer, Alexander, van Duijn, Cornelia M, Heiss, Gerardo, Metspalu, Andres, North, Kari E, Ingelsson, Erik, Nettleton, Jennifer A, van Dam, Rob M, Chasman, Daniel I, Nalls, Michael A, Plagnol, Vincent, Yu, Kai, Hernandez, Dena G, Sharma, Manu, Sheerin, Una-Marie, Saad, Mohamad, Simón-Sánchez, Javier, Schulte, Claudia, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Marques-Vidal, Pedro, Ben-Shlomo, Yoav, Berendse, Henk W, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, M., Rawal, Rajesh, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Cooper, J Mark, Manichaikul, Ani, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deloukas, Panos, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Dillman, Allissa, Durif, Frank, Byrne, Enda M, Wojczynski, Mary K, Dürr, Alexandra, Edkins, Sarah, Evans, Jonathan R, Foltynie, Thomas, Dong, Jing, Gardner, Michelle, Gibbs, J Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Vink, Jacqueline M, Harris, Clare, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Hershey, Milton S, Wurster, Isabel, Mätzler, Walter, Zhao, Jing Hua, Hudson, Gavin, Hunt, Sarah E, Huttenlocher, Johanna, Illig, Thomas, München, Helmholtz Zentrum, Jónsson, Pálmi V, Lambert, Jean-Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Burlutsky, George, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R, Morrison, Karen E, O' Sullivan, Sean S, Lahti, Jari, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, Pollak, Pierre, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Mikkilä, Vera, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Bettella, Francesco, Lemaitre, Rozenn N, Stockton, Joanna D, Strange, Amy, Talbot, Kevin, Tanner, M., Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Uitterlinden, André G, Velseboer, Daan, Eriksson, Joel, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Sabatier, Paul, Musani, Solomon K, Wood, Nicholas W, Hardy, John, Heutink, Peter, Brice, Alexis, Gasser, Thomas, Singleton, Andrew B, Singleton, Andrew, Cookson, Mark, Hernandez, Dena, Tanaka, Toshiko, Nalls, Michael, Zonderman, Alan, Ferrucci, Luigi, Johnson, Robert, Longo, Dan, O'Brien, Richard, Traynor, Bryan, Troncoso, Juan, Esko, Tõnu, Geller, Frank, van der Brug, Marcel, Zielke, Ronald, Weale, Michael, Ramasamy, Adaikalavan, Box, P. O., Luan, Jian'an, Hui, Jennie, Mägi, Reedik, Dimitriou, Maria, Garcia, Melissa E, Ho, Weang-Kee, Wright, Margaret J, Rose, Lynda M, Magnusson, Patrik Ke, Pedersen, Nancy L, Couper, David, Oostra, Ben A, Ikram, Mohammad Arfan, Tiemeier, Henning W, Uitterlinden, Andre G, van Rooij, Frank Ja, Barroso, Inês, Johansson, Ingegerd, Ganna, Andrea, Xue, Luting, Kaakinen, Marika, Milani, Lili, Power, Chris, Snieder, Harold, Stolk, Ronald P, Baumeister, Sebastian E, Biffar, Reiner, Gu, Fangyi, Bastardot, François, Paynter, Nina, Kutalik, Zoltán, Jacobs, David R, Forouhi, Nita G, Mihailov, Evelin, Lind, Lars, Lindgren, Cecilia, Michaëlsson, Karl, Morris, Andrew, Jensen, Majken, Khaw, Kay-Tee, Monda, Keri L, Luben, Robert N, Wang, Jie Jin, Männistö, Satu, Perälä, Mia-Maria, Kähönen, Mika, Lehtimäki, Terho, Viikari, Jorma, Mozaffarian, Dariush, Mukamal, Kenneth, Psaty, Bruce M, Amin, Najaf, Döring, Angela, Heath, Andrew C, Montgomery, Grant W, Dahmen, Norbert, Carithers, Teresa, Tucker, Katherine L, Boyd, Heather A, Melbye, Mads, Treur, Jorien L, Fischer, Krista, Mellström, Dan, Hottenga, Jouke Jan, Prokopenko, Inga, Tönjes, Anke, Kanoni, Stavroula, Lorentzon, Mattias, Houston, Denise K, Liu, Yongmei, Danesh, John, Biological Psychology, Nutrition and Health, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, The, Coffee, Cornelis, MC, Byrne, Enda, Esko, Tonu, Nalls, MA, Hyppönen, Elina, Chasman, DI, The Coffee and Caffeine Genetics Consortium, International Parkinson's Disease Genomics Consortium (IPDGC), UK Brain Expression Consortium (UKBEC), North American Brain Expression Consortium (NABEC), Epidemiology, Surgery, Public Health, Cell biology, Hematology, Clinical Genetics, Internal Medicine, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), ANS - Amsterdam Neuroscience, Neurology, Graduate School, Pediatric surgery, VU University medical center, NCA - neurodegeneration, Human genetics, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health
Subjects: INVOLVEMENT, Netherlands Twin Register (NTR), GCKR protein, human, PROTEIN, Genome-wide association study, VARIANTS, genetics [Brain-Derived Neurotrophic Factor], chemistry.chemical_compound, 0302 clinical medicine, Polymorphism (computer science), genetics [Adaptor Proteins, Signal Transducing], BINDING, BRAIN, Genetics, 0303 health sciences, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Psychiatry and Mental health, Phenotype, genetics [Polymorphism, Single Nucleotide], genetics [Cytochrome P-450 CYP1A2], Caffeine, CAFFEINE, Single-nucleotide polymorphism, Biology, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Cytochrome P-450 CYP1A2, SNP, Humans, ddc:610, Allele, genetics [Basic Helix-Loop-Helix Leucine Zipper Transcription Factors], Molecular Biology, 030304 developmental biology, Adaptor Proteins, Signal Transducing, MLXIPL protein, human, RECEPTOR, Brain-Derived Neurotrophic Factor, Coffea, ta1182, Feeding Behavior, biology.organism_classification, ta3124, BDNF, chemistry, Behavioral medicine, Developmental Psychopathology, 030217 neurology & neurosurgery, GLUCOKINASE, metabolism [Coffea], Genome-Wide Association Study
Abstract: Contains fulltext : 155360.pdf (Publisher’s version ) (Closed access) Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P
Published: 2015
Full Text: View/download PDF

43. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author: Niina Eklund, Robert C. Kaplan, Niek Verweij, Marcus Richards, Nancy L. Heard-Costa, Angelo Tremblay, Lu Qi, Andres Metspalu, Mark A. Sarzynski, Charleston W. K. Chiang, Tõnu Esko, Jaana Lindström, Pirro G. Hysi, Torben Hansen, James F. Wilson, Serena Sanna, Marie-Claude Vohl, Lynda M. Rose, Daniele Cusi, Megan T. Smith, Anne U. Jackson, Jing Hua Zhao, Anubha Mahajan, Nele Friedrich, Marcel Bruinenberg, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Weihua Zhang, Lavinia Paternoster, Jenny van Dongen, Torben Jørgensen, Aarno Palotie, Jana V. van Vliet-Ostaptchouk, Martin Farrall, Konstantin Strauch, Jan Smit, Zoltán Kutalik, Anne E. Justice, Elisabeth Widen, Tuomo Rankinen, Timo A. Lakka, Maria Dimitriou, Louis Pérusse, Peter J. van der Most, Yun Ju Sung, George Dedoussis, Caroline Hayward, Tom Wilsgaard, Peter P. Pramstaller, Maria Karaleftheri, Seppo Koskinen, Clive Osmond, Panos Deloukas, David J. Hunter, Kathleen Stirrups, Nicola Glorioso, Andrew T. Hattersley, Hugh Watkins, Sven Bergmann, Eric Boerwinkle, Catharina A. Hartman, Anke Tönjes, Daniel I. Chasman, May E. Montasser, Alan James, Ben A. Oostra, Nigel W. Rayner, Massimo Mangino, Ron T. Gansevoort, Cristina Barlassina, Johanna Kuusisto, Andrew A. Hicks, Roberto Lorbeer, Tomi Laitinen, Narisu Narisu, Stefan R. Bornstein, Gemma Cadby, Johan G. Eriksson, Gudmar Thorleifsson, Erika Salvi, Jari Lahti, Cornelia M. van Duijn, Janina M. Jeff, Heather M. Stringham, Bruce M. Psaty, Thomas W. Winkler, Paul M. Ridker, Unnur Thorsteinsdottir, Lyle J. Palmer, Alexander Teumer, Jürgen Gräßler, Allan Linneberg, Francesca D'Avila, Markku Heliövaara, Harald Grallert, Ivana Kolcic, Kari E. North, Eleftheria Zeggini, James S. Pankow, Alena Standáková, Marjo-Riitta Järvelin, Ozren Polasek, Krista Fischer, Valeriya Lyssenko, Thorkild I. A. Sørensen, André G. Uitterlinden, Stavroula Kanoni, Caroline S. Fox, Sophie R. Wang, Treva Rice, Maria Grazia Pilia, Olli T. Raitakari, Claudia Langenberg, Thomas Sparsø, Emmanouil Tsafantakis, Irene Pichler, Kathy Ryan, Eero Jokinen, Mika Kähönen, Leif Groop, Irene Mateo Leach, Gabriele Müller, Annette Peters, Peter Vollenweider, Oddgeir L. Holmen, David Schlessinger, Paul Knekt, M. Carola Zillikens, Evelin Mihailov, Erkki Vartiainen, Nicholas J. Wareham, Francis S. Collins, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Joel N. Hirschhorn, Frank B. Hu, Janina S. Ried, Valgerdur Steinthorsdottir, Shapour Jalilzadeh, Peter Kovacs, Anuj Goel, Pim van der Harst, Peter Schwarz, Mathias Gorski, Jorma Viikari, Uwe Völker, Cecilia M. Lindgren, Theodosios Kyriakou, Morris A. Swertz, Inga Prokopenko, Ken K. Ong, Leena Kinnunen, Markus Perola, Kristian Hveem, Matthias Blüher, Rebecca Mills, Albertine J. Oldehinkel, Anders Hamsten, Mattias Lorentzon, Joel Eriksson, Karen L. Mohlke, Rasmus Ribel-Madsen, Pekka Jousilahti, Paolo Manunta, Eva Albrecht, Jeffrey R. O'Connell, Wendy L. McArdle, Amy J. Swift, Dorret I. Boomsma, Harry Campbell, Fracensco Cucca, Aaron Isaacs, Andrew Wong, Georg Homuth, Laura M. Yerges-Armstrong, Carolina Medina-Gomez, Kay-Tee Khaw, Claes Ohlsson, Claude Bouchard, John Blangero, Aliki-Eleni Farmaki, Lorraine Southam, Anette P. Gjesing, Traci M. Bartz, Dabeeru C. Rao, Andrew P. Morris, David P. Strachan, Nita G. Forouhi, Eco J. C. de Geus, Jaakko Tuomilehto, Antti Jula, Ryan W. Walker, Mary F. Feitosa, Reedik Mägi, Aki S. Havulinna, Inger Njølstad, Alan R. Shudiner, Jennifer E. Huffman, Peter Lichtner, Richard N. Bergman, Mariaelisa Graff, Diana Kuh, Tim D. Spector, Robert Luben, Veikko Salomaa, Christian Gieger, Jaspal S. Kooner, Teresa Ferreira, Jennifer L. Bragg-Gresham, Sylvain Sebert, Terho Lehtimäki, Heikki A. Koistinen, Alexandra M. Lewin, Alexessander Couto Alves, Peter S. Chines, Lise Lotte N. Husemoen, Salome Scholtens, Yii-Der Ida Chen, Kati Kristiansson, Barbara McKnight, Sara M. Willems, Rainer Rauramaa, Satu Männistö, Stephan J. L. Bakker, Angela Döring, Audrey Y. Chu, Niels Grarup, Matti Uusitupa, Hannu Puolijoki, L. Adrienne Cupples, Veronique Vitart, Marie Neergaard Harder, Jouke-Jan Hottenga, Kari Stefansson, Alan F. Wright, Igor Rudan, Keri L. Monda, Jian'an Luan, Robert A. Scott, Albert Hofman, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Maija Hassinen, Sarah H. Wild, Iris M. Heid, Brenda W.J.H. Penninx, John C. Chambers, Claire Bellis, Nicholas D. Hastie, Ruth J. F. Loos, Martina Müller-Nurasyid, Johanne Marie Justesen, Gérard Waeber, Jennie Hui, Gonçalo R. Abecasis, Ishminder K. Kooner, Harold Snieder, Judith M. Vonk, Ioanna Tachmazidou, Ronald P. Stolk, Michael Stumvoll, Till Ittermann, Oluf Pedersen, Ingrid B. Borecki, Gonneke Willemsen, Jagvir Grewal, Markku Laakso, Arthur W. Musk, Eero Kajantie, Hans L. Hillege, Michael Boehnke, Cristina Venturini, Lili Milani, John Beilby, Fernando Rivadeneira, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Goel, Anuj [0000-0003-2307-4021], Jackson, Anne U [0000-0002-9672-2547], Kristiansson, Kati [0000-0003-4688-107X], Medina-Gomez, Carolina [0000-0001-7999-5538], Nolte, Ilja M [0000-0001-5047-4077], Prokopenko, Inga [0000-0003-1624-7457], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Beilby, John [0000-0002-4915-2254], Bergmann, Sven [0000-0002-6785-9034], Strachan, David P [0000-0001-7854-1366], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Energy & Sustainability Programme, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Children's Hospital, Lastentautien yksikkö, Clinicum, Institute for Molecular Medicine Finland, Behavioural Sciences, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Department of Medicine, Endokrinologian yksikkö, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, University of Helsinki, Leif Groop Research Group, Quantitative Genetics, HUS Children and Adolescents, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, School of Medicine / Clinical Medicine, School of Medicine / Biomedicine,School of Medicine / Clinical Nutrition, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg Gresham, Jennifer L., Van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Toñu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathia, Hayward, Caroline, Heard Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'An, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Pérusse, Loui, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Standáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blüher, Matthia, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S, Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, De Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G., Farmaki, Aliki Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niel, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Ander, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nichola, Hattersley, Andrew Tym, Havulinna, Aki S., Heliövaara, Markku, Hillege, Han, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E., Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosio, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattia, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, Mcardle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Müller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polašek, Ozren, Pramstaller, Peter P., Raitakari, Olli T, Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel Madsen, Rasmu, Rice, Treva K., Richards, Marcu, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J., Van Vliet Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie Claude, Vonk, Judith M., Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges Armstrong, Laura M., Zhao, Jing Hua, Carola Zillikens, M., Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Metspalu, Andre, Njølstad, Inger, Ohlsson, Clae, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Marku, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sørensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Pano, Van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., Mccarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Müller Nurasyid, Martina, Loos, Ruth J. F., Internal medicine, Psychiatry, EMGO - Mental health, Public Health, Epidemiology, Surgery, Internal Medicine, Erasmus MC other, and Child and Adolescent Psychiatry / Psychology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Statistical methods, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Mice, HEIGHT, Body Size, Mass index, 2. Zero hunger, Genetics, Principal Component Analysis, Multidisciplinary, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Anthropometry, Chemistry (all), Phenotype, Common, gene, body, shape, Multidisciplinary Sciences, Principal component analysis, Trait, Science & Technology - Other Topics, DIET-INDUCED OBESITY, Waist, Genotype, 515 Psychology, Science, EARLY-ONSET, Snp, BIOLOGY, HIP RATIO, Genome-wide association studies Statistical methods, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), MASS INDEX, DISEASE ASSOCIATIONS, RESOURCE, MD Multidisciplinary, Humans, GENOME-WIDE ASSOCIATION, Biochemistry, Genetics and Molecular Biology (all), Science & Technology, Models, Genetic, ta1184, FAT DISTRIBUTION, General Chemistry, ta3121, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Body mass index, Genome-Wide Association Study
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., published version, peerReviewed
Published: 2016
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44. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author: Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van Duijn, Cornelia M. McEniery CM, Wilkinson IB, Cockcroft JR, O'Shaughnessy KM, Newhouse SJ, Yasmin, Smith AV, Eiriksdottir G, Launer LJ, Sigurdsson S, Aspelund T, Gudnason V, De Bacquer D, Rietzschel ER, De Backer GG, Van Bortel L, De Buyzere ML, Segers P, Bekaert S, Gillebert TC, De Meyer T, Ferrucci L, Tanaka T, Johnson AD, Levy D, Benjamin EJ, Mitchell GF, Vita JA, Larson MG, Hamburg NM, Vasan RS, Isaacs A, Schut AF, Oostra BA, van Duijn CM, van Rijn MJ, Sie MP, Newman AB, Herrington DM, Andrews JS, Ding J, Sutton-Tyrrell KC, Harris TB, Howard TD, Liu Y, Parsa A, Shuldiner AR, McArdle PF, Gibson Q, Post WS, Dehghan A, Hofman A, Uitterlinden AG, Sijbrands EJ, Rivadeneira F, Mattace-Raso FU, Verwoert GC, Witteman JC, Scuteri A, Lakatta EG, Jewell E, Abecasis GR, Tarasov KV, Uda M, Najjar SS, Sanna S, Attwood T, Belz S, Braund P, Cambien F, Cooper J, Crisp-Hihn A, Deloukas P, Foad N, Eardman J, Goodall AH, Gracey J, Gray E, Gulde S, Gwilliams R, Heimerl S, Hengstenberg C, Jolley J, Krishnan U, Linsel-Nitschke P, Lloyd-Jones H, Lugauer I, Lundmark P, Maouche S, Moore JS, Muir D, Murray E, Nelson CP, Neudert J, Niblett D, O'Leary K, Ouwehand WH, Pollard H, Rankin A, Rice CM, Sager H, Samani NJ, Sambrook J, Schmitz G, Scholz M, Schroeder L, Schunkert H, Syvannen AC, Wallace C, Kathiresan S, Reilly MP, Erdmann J, Assimes TL, Boerwinkle E, Hall A, König IR, Laaksonen R, McPherson R, Thompson JR, Thorsteinsdottir U, Ziegler A, Absher D, Chen L, Cupples LA, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Voight BF, Wells GA, Assime TL, Holm H, Roberts R, Stewart AF, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Wild P, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel T, Barbalic M, Bis J, Chen IY, Cupples L, Demissie-Banjaw S, Folsom A, Glazer N, Harris T, Heckbert S, Lumley T, Marciante K, Morrison A, O' Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Uitterlinden A, Gretarsdottir S, Gulcher JR, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Fischer M, Grosshennig A, Lieb W, Stark K, Schreiber S, Wichmann HE, Aherrahrou Z, Bruse P, Doering A, Illig T, Klopp N, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Wagner AK, Willenborg C, Böhm BO, Dobnig H, Grammer TB, Hoffmann MM, Kleber M, März W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Guiducci C, Burtt N, Gabriel SB, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Dandona S, Jarinova O, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Yang YA, Stricker BH, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Willerson JT, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Gao X, Yang Q, O'Connell JR, Schmidt H, Ketkar S, Hwang SJ, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Siscovick D, Zillikens MC, Feitosa M, Province M, de Andrade M, Turner ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Coresh J, Schmidt R, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Felix SB, Watzinger N, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Reffelmann T, Redfield MM, Werdan K, Arnett DK, Blettner M, Friedrich N, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic N, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Vollenweider P, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Lightstone L, Scott J, Navis G, Elliott P, Kooner JS., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), University of Leicester, Department of Genetics [Leicester], Erasmus University Rotterdam, Netherlands Genomics Initiative, Department of Epidemiology and Biostatistics, School of Public Health, Zahedan University of Medical Sciences, Washington University in Saint Louis (WUSTL), Queen Mary University of London (QMUL), National Heart, Lung and Blood Institute, Partenaires INRAE, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne = University of Lausanne (UNIL), Department of Biostatistics [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Leiden University Medical Center (LUMC), Universiteit Leiden, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Department of Epidemiology, The Netherlands Cancer Institute, Department of Mathematics, Boston University [Boston] (BU), GlaxoSmithKline, Division of Community Health Sciences, St. George's, University of South Florida [Tampa] (USF), Universität Greifswald - University of Greifswald, University of Washington [Seattle], University of Tartu, Institute of Molecular and Cell Biology, Medical Research Council, Institut de Génomique, Centre National de Génotypage, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University Medical Center Groningen, Department of Genetics, University Medical Center Groningen [Groningen] (UMCG), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Massachusetts General Hospital [Boston], Centro de Regulación Genómica (CRG), Universitat Pompeu Fabra [Barcelona] (UPF), Università degli studi di Trieste = University of Trieste, Universität zu Lübeck = University of Lübeck [Lübeck], Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, The University of Western Australia (UWA), Department of Twin Research and Genetic Epidemiology, King's College London, London, University of Oxford, Medical University Graz, National Institute on Aging, Centre for population Health Sciences, University of Edinburgh, Uppsala University, Vrije Universiteit Amsterdam [Amsterdam] (VU), Western General Hospital, Harvard Medical School [Boston] (HMS), Brigham and Women's Hospital [Boston], University of Michigan System, University of Groningen, Ealing Hospital, School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, Medical Genetics Institute, Cedars-Sinai Medical Center, University of Tampere, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Split, The University of Texas Health Science Center at Houston (UTHealth), Johns Hopkins University (JHU), Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Swiss Institute of Bioinformatics [Lausanne] (SIB), Finnish Institute of Occupational Health, National Institute of Health and Welfare, University of Oulu, Lapland Central Hospital, University of Bristol [Bristol], Institute for Community Medicine, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), US National Institutes of Health, National Heart, Lung, and Blood Institute, European, Epidemiology, Internal Medicine, Public Health, Clinical Genetics, Université de Lausanne (UNIL), LeidenUniversity Medical Centre, University of Iceland, Università degli studi di Trieste, Universität zu Lübeck [Lübeck], University of Western Australia, University of Oxford [Oxford], VU University Amsterdam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Human genetics, Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Epidemiology and Data Science, Medical Research Council (MRC), Louise V., Wain, Germaine C., Verwoert, Paul F., O'Reilly, Gang, Shi, Toby, Johnson, Andrew D., Johnson, Murielle, Bochud, Kenneth M., Rice, Peter, Henneman, Albert V., Smith, Georg B., Ehret, Najaf, Amin, Martin G., Larson, Vincent, Mooser, David, Hadley, Marcus, Dörr, Joshua C., Bi, Thor, Aspelund, Tõnu, Esko, A. Cecile J. W., Janssen, Jing Hua, Zhao, Simon, Heath, Maris, Laan, Jingyuan, Fu, Giorgio, Pisti, Jian'An, Luan, Pankaj, Arora, Gavin, Luca, Pirastu, Nicola, Irene, Pichler, Anne U., Jackson, Rebecca J., Webster, Feng, Zhang, John F., Peden, Helena, Schmidt, Toshiko, Tanaka, Harry, Campbell, Wilmar, Igl, Yuri, Milaneschi, Jouke Jan, Hottenga, Veronique, Vitart, Daniel I., Chasman, Stella, Trompet, Jennifer L., Bragg Gresham, Behrooz Z., Alizadeh, John C., Chamber, Xiuqing, Guo, Terho, Lehtimäki, Brigitte, Kühnel, Lorna M., Lopez, Ozren, Polašek, Mladen, Boban, Christopher P., Nelson, Alanna C., Morrison, Vasyl, Pihur, Santhi K., Ganesh, Albert, Hofman, Suman, Kundu, Francesco U. S., Mattace Raso, Fernando, Rivadeneira, Eric J. G., Sijbrand, Andre G., Uitterlinden, Shih Jen, Hwang, Ramachandran S., Vasan, Thomas J., Wang, Sven, Bergmann, Peter, Vollenweider, Gérard, Waeber, Jaana, Laitinen, Anneli, Pouta, Paavo, Zitting, Wendy L., Mcardle, Heyo K., Kroemer, Uwe, Völker, Henry, Völzke, Nicole L., Glazer, Kent D., Taylor, Tamara B., Harri, Helene, Alavere, Toomas, Haller, Aime, Kei, Mari Liis, Tammesoo, Yurii, Aulchenko, Inês, Barroso, Kay Tee, Khaw, Pilar, Galan, Serge, Hercberg, Mark, Lathrop, Susana, Eyheramendy, Elin, Org, Siim, Sõber, Xiaowen, Lu, Ilja M., Nolte, Brenda W., Penninx, Tanguy, Corre, Corrado, Masciullo, Cinzia, Sala, Leif, Groop, Benjamin F., Voight, Olle, Melander, Christopher J., O'Donnell, Veikko, Salomaa, D'Adamo, ADAMO PIO, Antonella, Fabretto, Flavio, Faletra, Sheila, Ulivi, Fabiola Del Greco, M, Maurizio, Facheri, Francis S., Collin, Richard N., Bergman, John P., Beilby, Joseph, Hung, A., William Musk, Massimo, Mangino, So Youn, Shin, Nicole, Soranzo, Hugh, Watkin, Anuj, Goel, Anders, Hamsten, Pierre, Gider, Marisa, Loitfelder, Marion, Zeginigg, Dena, Hernandez, Samer S., Najjar, Pau, Navarro, Sarah H., Wild, Anna Maria, Corsi, Andrew, Singleton, Eco J. C., de Geu, Gonneke, Willemsen, Alex N., Parker, Lynda M., Rose, Brendan, Buckley, David, Stott, Marco, Orru, Manuela, Uda, Melanie M., van der Klauw, Weihua, Zhang, Xinzhong, Li, James, Scott, Yii Der Ida, Chen, Gregory L., Burke, Mika, Kähönen, Jorma, Viikari, Angela, Döring, Thomas, Meitinger, Gail, Davie, John M., Starr, Valur, Emilsson, Andrew, Plump, Jan H., Lindeman, Peter A. C., 't Hoen, Inke R., König, Janine F., Felix, Robert, Clarke, Jemma C., Hopewell, Halit, Ongen, Monique, Breteler, Stéphanie, Debette, Anita L., Destefano, Myriam, Fornage, Gary F., Mitchell, Nicholas L., Smith, Hilma, Holm, Kari, Stefansson, Gudmar, Thorleifsson, Unnur, Thorsteinsdottir, Nilesh J., Samani, Michael, Preu, Igor, Rudan, Caroline, Hayward, Ian J., Deary, H., Erich Wichmann, Olli T., Raitakari, Walter, Palma, Jaspal S., Kooner, Ronald P., Stolk, J., Wouter Jukema, Alan F., Wright, Dorret I., Boomsma, Stefania, Bandinelli, Ulf B., Gyllensten, James F., Wilson, Luigi, Ferrucci, Reinhold, Schmidt, Martin, Farrall, Tim D., Spector, Lyle J., Palmer, Jaakko, Tuomilehto, Arne, Pfeufer, Gasparini, Paolo, David, Siscovick, David, Altshuler, Ruth J. F., Loo, Daniela, Toniolo, Harold, Snieder, Christian, Gieger, Pierre, Meneton, Nicholas J., Wareham, Ben A., Oostra, Andres, Metspalu, Lenore, Launer, Rainer, Rettig, David P., Strachan, Jacques S., Beckmann, Jacqueline C. M., Witteman, Jeanette, Erdmann, Ko Willems van, Dijk, Eric, Boerwinkle, Michael, Boehnke, Paul M., Ridker, Marjo Riitta, Jarvelin, Aravinda, Chakravarti, Goncalo R., Abecasi, Vilmundur, Gudnason, Christopher Newton, Cheh, Daniel, Levy, Patricia B., Munroe, Bruce M., Psaty, Mark J., Caulfield, Dabeeru C., Rao, Martin D., Tobin, Paul, Elliott, Cornelia M., van Duijn, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcu, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Mari, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, Mcardle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Tooma, Keis, Aime, Tammesoo, Mari-Lii, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Ander, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, Jame, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thoma, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andre, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willem, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van, Duijn, Cornelia M., McEniery CM, Wilkinson, Ib, Cockcroft, Jr, O'Shaughnessy, Km, Newhouse, Sj, Yasmin, Smith, Av, Eiriksdottir, G, Launer, Lj, Sigurdsson, S, Aspelund, T, Gudnason, V, De Bacquer, D, Rietzschel, Er, De Backer, Gg, Van Bortel, L, De Buyzere, Ml, Segers, P, Bekaert, S, Gillebert, Tc, De Meyer, T, Ferrucci, L, Tanaka, T, Johnson, Ad, Levy, D, Benjamin, Ej, Mitchell, Gf, Vita, Ja, Larson, Mg, Hamburg, Nm, Vasan, R, Isaacs, A, Schut, Af, Oostra, Ba, van Duijn, Cm, van Rijn, Mj, Sie, Mp, Newman, Ab, Herrington, Dm, Andrews, J, Ding, J, Sutton-Tyrrell, Kc, Harris, Tb, Howard, Td, Liu, Y, Parsa, A, Shuldiner, Ar, Mcardle, Pf, Gibson, Q, Post, W, Dehghan, A, Hofman, A, Uitterlinden, Ag, Sijbrands, Ej, Rivadeneira, F, Mattace-Raso, Fu, Verwoert, Gc, Witteman, Jc, Scuteri, A, Lakatta, Eg, Jewell, E, Abecasis, Gr, Tarasov, Kv, Uda, M, Najjar, S, Sanna, S, Attwood, T, Belz, S, Braund, P, Cambien, F, Cooper, J, Crisp-Hihn, A, Deloukas, P, Foad, N, Eardman, J, Goodall, Ah, Gracey, J, Gray, E, Gulde, S, Gwilliams, R, Heimerl, S, Hengstenberg, C, Jolley, J, Krishnan, U, Linsel-Nitschke, P, Lloyd-Jones, H, Lugauer, I, Lundmark, P, Maouche, S, Moore, J, Muir, D, Murray, E, Nelson, Cp, Neudert, J, Niblett, D, O'Leary, K, Ouwehand, Wh, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Samani, Nj, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Schunkert, H, Syvannen, Ac, Wallace, C, Kathiresan, S, Reilly, Mp, Erdmann, J, Assimes, Tl, Boerwinkle, E, Hall, A, König, Ir, Laaksonen, R, Mcpherson, R, Thompson, Jr, Thorsteinsdottir, U, Ziegler, A, Absher, D, Chen, L, Cupples, La, Halperin, E, Li, M, Musunuru, K, Preuss, M, Schillert, A, Thorleifsson, G, Voight, Bf, Wells, Ga, Assime, Tl, Holm, H, Roberts, R, Stewart, Af, Fortmann, S, Go, A, Hlatky, M, Iribarren, C, Knowles, J, Myers, R, Quertermous, T, Sidney, S, Risch, N, Tang, H, Blankenberg, S, Zeller, T, Wild, P, Schnabel, R, Sinning, C, Lackner, K, Tiret, L, Nicaud, V, Bickel, C, Rupprecht, Hj, Perret, C, Proust, C, Münzel, T, Barbalic, M, Bis, J, Chen, Iy, Cupples, L, Demissie-Banjaw, S, Folsom, A, Glazer, N, Harris, T, Heckbert, S, Lumley, T, Marciante, K, Morrison, A, O' Donnell, Cj, Psaty, Bm, Rice, K, Rotter, Ji, Siscovick, D, Smith, N, Smith, A, Taylor, Kd, van Duijn, C, Volcik, K, Whitteman, J, Ramachandran, V, Uitterlinden, A, Gretarsdottir, S, Gulcher, Jr, Kong, A, Stefansson, K, Thorgeirsson, G, Andersen, K, Fischer, M, Grosshennig, A, Lieb, W, Stark, K, Schreiber, S, Wichmann, He, Aherrahrou, Z, Bruse, P, Doering, A, Illig, T, Klopp, N, Loley, C, Medack, A, Meisinger, C, Meitinger, T, Nahrstedt, J, Peters, A, Wagner, Ak, Willenborg, C, Böhm, Bo, Dobnig, H, Grammer, Tb, Hoffmann, Mm, Kleber, M, März, W, Meinitzer, A, Winkelmann, Br, Pilz, S, Renner, W, Scharnagl, H, Stojakovic, T, Tomaschitz, A, Winkler, K, Guiducci, C, Burtt, N, Gabriel, Sb, O'Donnell, Cj, Elosua, R, Peltonen, L, Salomaa, V, Schwartz, Sm, Melander, O, Altshuler, D, Dandona, S, Jarinova, O, Qu, L, Wilensky, R, Matthai, W, Hakonarson, Hh, Devaney, J, Burnett, M, Pichard, Ad, Kent, Km, Satler, L, Lindsay, Jm, Waksman, R, Knouff, Cw, Waterworth, Dm, Walker, Mc, Mooser, V, Epstein, Se, Rader, Dj, Wright, Bj, Balmforth, Aj, Ball, Sg, Smith, Nl, Felix, Jf, Morrison, Ac, Demissie, S, Glazer, Nl, Loehr, Lr, Rosamond, Wd, Bis, Jc, Folsom, Ar, Benjamin, E, Aulchenko, Y, Haritunians, T, Couper, D, Murabito, J, Yang, Ya, Stricker, Bh, Gottdiener, J, Chang, Pp, Wang, Tj, Rice, Km, Heckbert, Sr, Fox, Er, Willerson, Jt, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Gao, X, Yang, Q, O'Connell, Jr, Schmidt, H, Ketkar, S, Hwang, Sj, Teumer, A, Paré, G, Atkinson, Ej, Lohman, K, Cornelis, Mc, Probst-Hensch, Nm, Kronenberg, F, Tönjes, A, Hayward, C, Rampersaud, E, Mitchell, Bd, Arking, De, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, F, Metter, J, de Boer, Ih, Zillikens, Mc, Feitosa, M, Province, M, de Andrade, M, Turner, St, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, T, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, A, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Prokopenko, I, Wang, W, Coresh, J, Schmidt, R, Shlipak, Mg, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, C, Felix, Sb, Watzinger, N, Homuth, G, Aragam, J, Dörr, M, Zweiker, R, Lind, L, Rodeheffer, Rj, Greiser, Kh, Deckers, Jw, Stritzke, J, Lackner, Kj, Ingelsson, E, Kullo, I, Haerting, J, Reffelmann, T, Redfield, Mm, Werdan, K, Arnett, Dk, Blettner, M, Friedrich, N, Chambers, Jc, Zhang, W, Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, J, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Davey Smith, G, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, N, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, Homan van der Heide, Jj, Hepkema, Bg, Hernandez-Fuentes, M, Hypponen, E, Johnson, T, de Jong, Pe, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Munroe, Pb, Nordfors, L, Penninx, Bw, Perucha, E, Pouta, A, Roderick, Pj, Ruokonen, A, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Vollenweider, P, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Lightstone, L, Scott, J, Navis, G, Elliott, P, and Kooner, Js.
Subjects: Netherlands Twin Register (NTR), Linkage disequilibrium, pulse pressure, mean arterial pressure, genome-wide, [SDV]Life Sciences [q-bio], Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, 030204 cardiovascular system & hematology, Linkage Disequilibrium, 0302 clinical medicine, RELEVANCE, CardioGram, Medicine and Health Sciences, Genetics & Heredity, ddc:616, Genetics, 0303 health sciences, Genome-wide association, 11 Medical And Health Sciences, Arteries, ADRENERGIC-RECEPTOR TRAFFICKING, Pulse pressure, EchoGen consortium, Hypertension, HEART-FAILURE, arterial pressure, Case-Control Studie, Life Sciences & Biomedicine, Human, circulatory and respiratory physiology, medicine.medical_specialty, Mean arterial pressure, Arterie, AortaGen Consortium, Cardiogenics consortium, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Follow-Up Studie, 03 medical and health sciences, Internal medicine, medicine, Humans, cardiovascular diseases, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, HYPERTENSION, MORTALITY, Case-control study, CARDIOVASCULAR-DISEASE RISK, 06 Biological Sciences, GENE, MICE, Endocrinology, Blood pressure, CKDGen consortium, Genetic Loci, Case-Control Studies, KidneyGen consortium, CHARGE Consortium Heart Failure Working Group, LifeLines Cohort Study, Developmental Biology, Follow-Up Studies, Genome-Wide Association Study
Abstract: Les affiliations des 100 premiers auteurs sont renseignées dans la notice. Les affiliations des autres auteurs sont disponibles à la fin de la publication.; International audience; Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Published: 2016
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45. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies

Author: Ndeye Coumba Ndiaye, Vilmundur Gudnason, Daniela Ruggiero, Maria Pina Concas, Andrew D. Johnson, Seung Hoan Choi, Caterina Barbieri, Albert V. Smith, Teresa Nutile, Giovanni Battista Maestrale, Sophie Visvikis-Siest, Maria G. Stathopoulou, Rossella Sorice, Stéphanie Debette, Marina Ciullo, Anne-Louise Leutenegger, Cinzia Sala, Vasiliki Lagou, John Victor Lamont, Ramachandran S. Vasan, Erik Ingelsson, Peter Fitzgerald, Sudha Seshadri, Céline Bellenguez, Daniela Toniolo, Ci Song, Peter Kovacs, Anita L. DeStefano, Mario Pirastu, Anke Tönjes, Michela Traglia, Lars Lind, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche (CNR), Uppsala Universitet [Uppsala], Karolinska Institutet [Stockholm], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], IRCCS San Raffaele Scientific Institute [Milan, Italie], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Faculté de Pharmacie [Nancy], Université de Lorraine (UL), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Randox Laboratories, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), UL, IGEPCV, Choi, Seung Hoan, Ruggiero, Daniela, Sorice, Rossella, Song, Ci, Nutile, Teresa, Vernon Smith, Albert, Concas, Maria Pina, Traglia, Michela, Barbieri, Caterina, Ndiaye, Ndeye Coumba, Stathopoulou, Maria G., Lagou, Vasiliki, Maestrale, Giovanni Battista, Sala, Cinzia, Debette, Stephanie, Kovacs, Peter, Lind, Lar, Lamont, John, Fitzgerald, Peter, Tönjes, Anke, Gudnason, Vilmundur, Toniolo, Daniela, Pirastu, Mario, Bellenguez, Celine, Vasan, Ramachandran S., Ingelsson, Erik, Leutenegger, Anne-Louise, Johnson, Andrew D., Destefano, Anita L., Visvikis-Siest, Sophie, Seshadri, Sudha, Ciullo, Marina, and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Vascular Endothelial Growth Factor A, Cell signaling, Medicin och hälsovetenskap, Cancer Research, Physiology, Angiogenesis, Gene Expression, Genome-wide association study, Signal transduction, Medical and Health Sciences, Database and Informatics Methods, chemistry.chemical_compound, Mathematical and Statistical Techniques, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Chromosomes, Human, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, Ecology, Chromosome Biology, Genomics, Hematology, Single Nucleotide, VEGF signaling, Genomic Databases, VEGF, Phenotype, Body Fluids, 3. Good health, Vascular endothelial growth factor, Blood, 030220 oncology & carcinogenesis, Physical Sciences, Anatomy, Cellular Types, Statistics (Mathematics), Research Article, Human, Platelets, lcsh:QH426-470, Evolution, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Research and Analysis Methods, Genome Complexity, Chromosome, Polymorphism, Single Nucleotide, Chromosomes, White People, 03 medical and health sciences, Behavior and Systematics, Genetic, Genome-Wide Association Studies, Humans, Statistical Methods, 1000 Genomes Project, Polymorphism, Gene, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Genome-Wide Association Study, Genetic Loci, Blood Cells, Biology and Life Sciences, Computational Biology, Human Genetics, Cell Biology, Genome Analysis, Ecology, Evolution, Behavior and Systematic, Introns, lcsh:Genetics, Biological Databases, 030104 developmental biology, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Expression quantitative trait loci, Mathematics, Meta-Analysis
Abstract: Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79x10-13), rs74506613 (JMJD1C, P = 1.17x10-19), rs4782371 (ZFPM1, P = 1.59x10-9) and rs2639990 (ZADH2, P = 1.72x10-8), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52x10-18; rs7043199, VLDLR-AS1, P = 5.12x10-14) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39x10-1467; rs1740073, C6orf223, P = 2.34x10-17; rs6993770, ZFPM2, P = 2.44x10-60; rs2375981, KCNV2, P = 1.48x10-100). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases., Author Summary Vascular Endothelial Growth Factor (VEGF) is a protein with a fundamental role in development of vascular system. The protein, produced by many types of cells, is released in the blood. High levels of VEGF have been observed in different pathological conditions especially in cancer, cardiovascular, and inflammatory diseases. Therefore, identifying the genetic factors influencing VEGF levels is important for predicting and treating such pathologies. The number of genetic variants associated with VEGF levels has been limited. To identify new loci, we have performed a Genome Wide Association Study meta-analysis on a sample of more than 16,000 individuals from 10 cohorts, using a high-density genetic map. This analysis revealed 10 variants associated with VEGF circulating levels, 6 of these being novel associations. The 10 variants cumulatively explain more than 50% of the variability of VEGF serum levels. Our analyses have identified genes known to be involved in angiogenesis related diseases and genes implicated in platelet metabolism, suggesting the importance of links between this process and VEGF regulation. Overall, these data have improved our understanding of the genetic variation underlying circulating VEGF levels. This in turn could guide our response to the challenge posed by various VEGF-related pathologies.
Published: 2016
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46. Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Author: W. H. Linda Kao, Nicole Probst-Hensch, Florian Ernst, Paul Mitchell, Christa Meisinger, Florian Kronenberg, Sharon L.R. Kardia, Paul M. Ridker, Vilmundur Gudnason, Jeanette S. Andrews, Ming-Huei Chen, Frank B. Hu, Jean-Charles Lambert, Mario Pirastu, Ozren Polasek, Xiaoyi Gao, Sven Bergmann, Catherine Helmer, Wilmar Igl, Jie Jin Wang, Barry I. Freedman, Anke Tönjes, Jacqueline C. M. Witteman, Sheila Ulivi, Conall M. O'Seaghdha, Mika Kähönen, Mariza de Andrade, Daniel I. Chasman, Meredith C. Foster, Rossella Sorice, Mathias Gorski, Eric Boerwinkle, Karlhans Endlich, Maksim Struchalin, Bernhard K. Krämer, Bénédicte Stengel, Caroline Hayward, Giorgio Pistis, Andres Metspalu, Peter Kovacs, Jorma Viikari, Guo Li, Cristian Pattaro, Adrienne Tin, Igor Rudan, Christian Gieger, Mary F. Feitosa, Stephen T. Turner, Gary C. Curhan, Shamika Ketkar, Ian Ford, Peter Vollenweider, Wolfgang Koenig, Madhumathi Rao, Iris M. Heid, Stuart K. Kim, Heather E. Wheeler, Matthias Olden, Hinco J. Gierman, Alex S. F. Doney, Lenore J. Launer, Mladen Boban, Georg Homuth, Paolo Gasparini, Harshal Deshmukh, Henry Völzke, Daniela Ruggiero, Medea Imboden, Elizabeth J. Atkinson, Ben A. Oostra, Stefan Coassin, Ute Nöthlings, Marilyn C. Cornelis, David S. Siscovick, Yongmei Liu, Gian Andri Thun, Gunnar Jacobs, Franco Giulianini, Uwe Völker, Tõnu Esko, Alexander Teumer, Jeffrey R. O'Connell, Brendan M. Buckley, Heyo K. Kroemer, Albert V. Smith, Ulf Gyllensten, Federico Murgia, Man Li, Harry Campbell, Antonietta Robino, Abbas Dehghan, Inga Prokopenko, Shih-Jen Hwang, Sylvia Stracke, Michael Stumvoll, Alan R. Shuldiner, Christian Fuchsberger, Claudia Hundertmark, Luigi Ferrucci, David Ellinghaus, Laura Portas, Caroline S. Fox, Afshin Parsa, Carsten A. Böger, Toshiko Tanaka, Terho Lehtimäki, Ayse Demirkan, James F. Wilson, Elizabeth G. Holliday, Yurii S. Aulchenko, Murielle Bochud, Helen M. Colhoun, Jingzhong Ding, Nicole L. Glazer, Rainer Rettig, Bernhard Paulweber, Margherita Cavalieri, Andre Franke, Ingrid B. Borecki, Olli T. Raitakari, Josef Coresh, Tamara B. Harris, Sarah H. Wild, Reinhold Schmidt, Ching-Ti Liu, Zoltán Kutalik, André G. Uitterlinden, J. Wouter Jukema, Helena Schmidt, Martin Adam, Audrey Y. Chu, Fernando Rivadeneira, Cornelia M. van Duijn, Braxton D. Mitchell, Gudny Eiriksdottir, Tatijana Zemunik, Andrew D. Johnson, Ghazal Zaboli, Reiner Biffar, Thor Aspelund, Cinzia Sala, Peter P. Pramstaller, Veronique Vitart, Michael A. Province, Anna Köttgen, Nicholas D. Hastie, Daniel Taliun, Marina Ciullo, Cosetta Minelli, Kurt Lohman, Matthias Nauck, Thomas Illig, Alan F. Wright, Albert Hofman, Colin N. A. Palmer, Daniela Toniolo, Qiong Yang, Lina Zgaga, Åsa Johansson, Margot Haun, Stella Trompet, Aaron Isaacs, Reedik Mägi, Tiit Nikopensius, Epidemiology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Internal Medicine, Chasman, Di, Fuchsberger, C, Pattaro, C, Teumer, A, Böger, Ca, Endlich, K, Olden, M, Chen, Mh, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, Mc, O'Seaghdha, Cm, Glazer, N, Isaacs, A, Liu, Ct, Smith, Av, O'Connell, Jr, Struchalin, M, Tanaka, T, Li, G, Johnson, Ad, Gierman, Hj, Feitosa, Mf, Hwang, Sj, Atkinson, Ej, Lohman, K, Cornelis, Mc, Johansson, A, Tönjes, A, Dehghan, A, Lambert, Jc, Holliday, Eg, Sorice, R, Kutalik, Z, Lehtimäki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, Ay, Murgia, F, Trompet, S, Imboden, M, Coassin, S, Pistis, G, Cardiogram, Consortium, Icbp, Consortium, the CARe, Consortium, Wtccc2, Harris, Tb, Launer, Lj, Aspelund, T, Eiriksdottir, G, Mitchell, Bd, Boerwinkle, E, Schmidt, H, Cavalieri, M, Rao, M, Hu, F, Demirkan, A, Oostra, Ba, de Andrade, M, Turner, St, Ding, J, Andrews, J, Freedman, Bi, Giulianini, F, Koenig, W, Illig, T, Meisinger, C, Gieger, C, Zgaga, L, Zemunik, T, Boban, M, Minelli, C, Wheeler, He, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Nöthlings, U, Jacobs, G, Biffar, R, Ernst, F, Homuth, G, Kroemer, Hk, Nauck, M, Stracke, S, Völker, U, Völzke, H, Kovacs, P, Stumvoll, M, Mägi, R, Hofman, A, Uitterlinden, Ag, Rivadeneira, F, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, Jj, Stengel, B, Ruggiero, D, Bergmann, S, Kähönen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, Antonietta, Krämer, Bk, Portas, L, Ford, I, Buckley, Bm, Adam, M, Thun, Ga, Paulweber, B, Haun, M, Sala, C, Mitchell, P, Ciullo, M, Kim, Sk, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, Paolo, Pirastu, M, Jukema, Jw, Probst Hensch, Nm, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, Ar, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, D, van Duijn, Cm, Borecki, Ib, Kardia, Sl, Liu, Y, Curhan, Gc, Rudan, I, Gyllensten, U, Wilson, Jf, Franke, A, Pramstaller, Pp, Rettig, R, Prokopenko, I, Witteman, J, Hayward, C, Ridker, Pm, Parsa, A, Bochud, M, Heid, Im, Kao, Wl, Fox, C, and Köttgen, A.
Subjects: Candidate gene, Amino Acid Transport Systems, Basic/genetics, Genome-wide association study, Gene, Genome, Inhibin-beta Subunits/genetics, GWAS, kidney, eGFR, Genetics (clinical), Inhibin-beta Subunits, Glomerular Filtration Rate/genetics, Genetics, 0303 health sciences, Genetic Predisposition to Disease/genetics, Association Studies Articles, 030305 genetics & heredity, Intracellular Signaling Peptides and Proteins, General Medicine, Low Density Lipoprotein Receptor-Related Protein-2/genetics, Polymorphism, Single Nucleotide/genetics, LRP2, 3. Good health, Low Density Lipoprotein Receptor-Related Protein-2, Genome-Wide Association Study/methods, Single Nucleotide/genetics, Glomerular Filtration Rate, Fusion Regulatory Protein 1, Heavy Chain, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genome-Wide Association Studies, Humans, SNP, Genetic Predisposition to Disease, ddc:610, Membrane Proteins/genetics, Polymorphism, Molecular Biology, 030304 developmental biology, Genetic association, Fusion Regulatory Protein 1, Heavy Chain/genetics, Fusion Regulatory Protein 1, Genes, Kidney Function, Membrane Proteins, ta3121, Amino Acid Transport Systems, Basic, Amino Acid Transport Systems, Basic/genetics, Heavy Chain/genetics, Intracellular Signaling Peptides and Proteins/genetics, Candidate Disease Gene, Genome-Wide Association Study
Abstract: In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
Published: 2012

47. Genome-wide physical activity interactions in adiposity ― a meta-analysis of 200,452 adults

Author: Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, Tuomas O Kilpeläinen, Molecular Genetics, Epidemiology, Radiology & Nuclear Medicine, Erasmus MC other, Internal Medicine, Erasmus School of Economics, and Department of Finance
Subjects: Epigenomics, Male, 0301 basic medicine, Cancer Research, Published Erratum, lcsh:QH426-470, Genotype, Physical activity, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Computational biology, Biology, Genome, Body Mass Index, PAGE Consortium, 03 medical and health sciences, Text mining, Genetics, Humans, Genetic Predisposition to Disease, Obesity, Exercise, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Adiposity, 0604 Genetics, Waist-Hip Ratio, business.industry, Correction, lcsh:Genetics, 030104 developmental biology, Meta-analysis, CHARGE Consortium, Female, EPIC-InterAct Consortium, Waist Circumference, business, Developmental Biology, Genome-Wide Association Study
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Published: 2017

48. Widely used commercial ELISA does not detect preHP-2, but recognizes properdin as a potential second member of the zonulin family

Author: Michael Stumvoll, Henrike O. Heyne, Dorit Schleinitz, Rachel Freire, Peter Kovacs, Maria Fiorentino, Alessio Fasano, Lucas Scheffler, Christian Ihling, John T. Heiker, Anke Tönjes, and Alyce Crane
Subjects: Intestinal permeability, biology, medicine.diagnostic_test, medicine.drug_class, Haptoglobin, Zonulin, medicine.disease, Monoclonal antibody, Molecular biology, Western blot, Polyclonal antibodies, biology.protein, medicine, Properdin, Antibody
Abstract: BACKGROUNDThere is increasing evidence for the role of impaired intestinal permeability in obesity and associated metabolic diseases. Zonulin is an established serum marker for intestinal permeability and identical to pre-haptoglobin2. Here, we aimed to investigate the relationship between circulating zonulin and metabolic traits related to obesity.METHODSSerum zonulin was measured by using a widely used commercial ELISA kit in 376 subjects from the metabolically well-characterized cohort of Sorbs from Germany. In addition, haptoglobin genotype was determined in DNA samples from all study subjects.RESULTSAs zonulin concentrations did not correlate to the haptoglobin genotypes, we investigated the specificity of the zonulin ELISA assay using antibody capture experiments, mass spectrometry and Western blot analysis. Using serum samples that gave the highest or lowest ELISA signals, we detected several proteins that are likely to be captured by the antibody in the present kit. However, none of these proteins corresponds to pre-haptoglobin2. We used increasing concentrations of recombinant pre-haptoglobin 2 and complement C3 as one of the representative captured proteins and the ELISA kit did not detect either. Western blot analysis using both the polyclonal antibodies used in this kit and monoclonal antibodies rose against zonulin showed a similar protein recognition pattern but with different intensity of detection. The protein(s) measured using the ELISA kit was (were) significantly increased in patients with diabetes and obesity and correlated strongly with markers of the lipid and glucose metabolism. Combining mass spectrometry and Western blot analysis using the polyclonal antibodies used in the ELISA kit, we identified properdin as another member of the zonulin family.CONCLUSIONSOur study suggests that the zonulin ELISA does not recognize pre-haptoglobin 2, rather structural (and possibly functional) analogue proteins belonging to the mannose-associated serine protease family, with properdin being the most likely possible candidate.
Published: 2017
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49. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

Author: Amélie Bonnefond, Nancy L. Heard-Costa, Julius S. Ngwa, Jennifer E. Huffman, Tanja B. Grammer, Jaakko Tuomilehto, Lu Qi, Nicholas G. Martin, Massimo Mangino, Henrik Vestergaard, Penny Gordon-Larsen, Reedik Mägi, Natalia V. Rivera, Charles Kooperberg, Alain G. Bertoni, Sarah H. Wild, Robert Luben, Veikko Salomaa, Claude Bouchard, Lynda M. Rose, Patricia A. Peyser, Graciela E. Delgado, Jessica D. Faul, Tuija Tammelin, John C. Chambers, Tsegaselassie Workalemahu, Kari E. North, David J. Porteous, Peter Vollenweider, Kennet Harald, Claire Bellis, Serena Sanna, Nicholas D. Hastie, Robert J. Klein, Marie-Claude Vohl, Ruth J. F. Loos, Jian Gong, Igor Rudan, Unhee Lim, Christopher A. Haiman, Martina Müller-Nurasyid, Konstantin Strauch, Mark A. Sarzynski, Albert V. Smith, Mark Walker, Tapani Ebeling, Göran Hallmans, Nicole Dueker, Caroline S. Fox, Sven Bergmann, Keri L. Monda, Thorkild I. A. Sørensen, André G. Uitterlinden, Johanne Marie Justesen, Aki S. Havulinna, Torben Hansen, Ivana Kolcic, Cecilia M. Lindgren, Marcel den Hoed, Richard N. Bergman, Mariaelisa Graff, Alan R. Shuldiner, Dorota Pasko, James F. Wilson, John Whitfield, Joel Eriksson, Jaspal S. Kooner, Mette Hollensted, Winfried März, Gonçalo R. Abecasis, Weihua Zhang, Harold Snieder, Rajesh Rawal, Tao Huang, Åsa Johansson, Lydia Quaye, Ying Wu, Benjamin Lehne, Matthias Nauck, Caroline Hayward, Linda S. Adair, Michel Marre, Tanguy Corre, Alan James, Frida Renström, Jian'an Luan, Zoltán Kutalik, Kurt Lohman, Jennifer A. Smith, Mao Fu, Jennifer L. Bragg-Gresham, Tamara B. Harris, Claudia Langenberg, Tõnu Esko, Mattias Lorentzon, Ken K. Ong, Blair H. Smith, Fabio Busonero, Alan F. Wright, Gemma Cadby, Andrew D. Johnson, Steve Buyske, Anubha Mahajan, Antonella Mulas, Gérard Waeber, Lori L. Bonnycastle, Daniel I. Chasman, Jennie Hui, Audrey Y. Chu, Uwe Völker, Albertine J. Oldehinkel, Jing Hua Zhao, Robert A. Scott, Ilja M. Nolte, Loic LeMarchand, Yu-Ching Cheng, David P. Strachan, Jie Huang, Gerard van Grootheest, John D. Eicher, Marcus E. Kleber, Francis S. Collins, Cornelia M. van Duijn, Timothy M. Frayling, Pau Navarro, Leo-Pekka Lyytikäinen, Cinzia Sarti, Paul M. Ridker, John-Olov Jansson, Shafqat Ahmad, Philippe Froguel, Albert Hofman, Inga Prokopenko, Vilmundur Gudnason, Anne U. Jackson, David R. Weir, Lyle J. Palmer, Alexander Teumer, Ulf Gyllensten, Mette Aadahl, Niels Grarup, Beverley Balkau, Oluf Pedersen, Cornelia Huth, Dorret I. Boomsma, Harry Campbell, Charlotte Huppertz, Ingrid B. Borecki, Juha Auvinen, Soren Snitker, Yuri Milaneschi, Iris M. Heid, Barbara Thorand, Wouter J. Peyrot, Lavinia Paternoster, Sian-Tsung Tan, Anne E. Justice, Dena G. Hernandez, Marcus Dörr, Nicholas J. Wareham, Marilyn C. Cornelis, Claes Ohlsson, Amy J. Swift, Ozren Polasek, Brenda W.J.H. Penninx, James E. Hayes, Stephanie A. Bien, Jana V. van Vliet-Ostaptchouk, Eric Boerwinkle, Louis Pérusse, Peter J. van der Most, Ulrike Peters, Pirjo Komulainen, Lynne J. Hocking, Catharina A. Hartman, William R. Scott, Jeffrey R. O'Connell, Stefania Bandinelli, Tuomo Rankinen, Timo A. Lakka, Leena Kinnunen, Markus Perola, John Blangero, Sharon L.R. Kardia, Veronique Vitart, Mika Kähönen, Marie Neergaard Harder, Diana Kuh, Kai Savonen, Kristin L. Young, Jeremiah Perez, Nina Hutri-Kähönen, George Davey Smith, Toshiko Tanaka, Barbara Sternfeld, Jennifer A. Nettleton, Jouke-Jan Hottenga, Christian Gieger, Gonneke Willemsen, Soren Brage, Mika Kivimäki, Lucia A. Hindorff, Steve Sidney, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Loic Yengo, Markku Laakso, Yongmei Liu, Arthur W. Musk, Harald Grallert, Kirsti Kvaløy, Rainer Rauramaa, Satu Männistö, Tuomas O. Kilpeläinen, M. Carola Zillikens, Hannu Puolijoki, Luting Xue, Oddgeir L. Holmens, Sandosh Padmanabhan, Inês Barroso, Ching-Ti Liu, L. Adrienne Cupples, Judith B. Borja, Karen L. Mohlke, Matthias Olden, Henry Völzke, Myriam Fornage, Michael Boehnke, Pedro Marques-Vidal, John Beilby, Fernando Rivadeneira, Maija Hassinen, Najaf Amin, Kristian Hveem, Gudny Eiriksdottir, Lenore J. Launer, Johanna Kuusisto, Dorothée Thuillier, Heather M. Stringham, Sven Gläser, Min A. Jhun, Marjo-Riitta Järvelin, Niha Zubair, Annette Peters, Llilda Barata, Paula J. Griffin, Markus Juonala, Wei Zhao, Andres Metspalu, Christina Holzapfel, Lawrence F. Bielak, Thomas W. Winkler, Alena Stančáková, Anke Tönjes, Narisu Narisu, David Hadley, Peter S. Chines, Andrew Wong, Günther Silbernagel, Kati Kristiansson, Eco J. C. de Geus, Grant W. Montgomery, Elise Lim, Laura J. Rasmussen-Torvik, Terho Lehtimäki, Heikki A. Koistinen, Meena Kumari, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Reija Männikkö, Jonathan Marten, Olli T. Raitakari, Mary F. Feitosa, Paul W. Franks, Kristine Færch, Mark I. McCarthy, Marleen H.M. de Moor, Joel N. Hirschhorn, Toomas Haller, Graff, Mariaelisa [0000-0001-6380-1735], Young, Kristin L [0000-0003-0070-6145], Winkler, Thomas W [0000-0003-0292-5421], Heard-Costa, Nancy L [0000-0001-9730-0306], Renström, Frida [0000-0001-6053-298X], Barroso, Inês [0000-0001-5800-4520], Strachan, David P [0000-0001-7854-1366], Liu, Ching-Ti [0000-0002-0703-0742], Klein, Robert J [0000-0003-3539-5391], Apollo - University of Cambridge Repository, University of Helsinki, Institute for Molecular Medicine Finland, Quantitative Genetics, Clinicum, Department of Medicine, Endokrinologian yksikkö, HUS Internal Medicine and Rehabilitation, Complex Disease Genetics, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Edwards, Todd L., Biological Psychology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Clinical Child and Family Studies, APH - Methodology, School of Medicine / Biomedicine, Public and occupational health, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Epidemiology, Medical Microbiology & Infectious Diseases, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Internal Medicine
Subjects: Netherlands Twin Register (NTR), Epigenomics, Male, Genome-wide association study, genome, obesity, BMI, Body Mass Index, 0302 clinical medicine, Cell Signaling, Public and Occupational Health, GENE-EXPRESSION, Adiposity, Genetics & Heredity, ADIPOCYTE DIFFERENTIATION, 1184 Genetics, developmental biology, physiology, Genomics, Functional Genomics, 3. Good health, Meta-analysis, Physical Sciences, REACTIVE PROTEIN-LEVELS, Waist Circumference, Statistics (Mathematics), Waist, Genotype, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Single-nucleotide polymorphism, Locus (genetics), BINDING PROTEIN, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genome-Wide Association Studies, Genetics, Humans, Statistical Methods, Molecular Biology, Exercise, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Science & Technology, ASSOCIATION METAANALYSIS, Physical activity, ta1184, Biology and Life Sciences, Computational Biology, Physical Activity, 030104 developmental biology, Genetic Loci, Body mass index, Mathematics, 030217 neurology & neurosurgery, Meta-Analysis, Developmental Biology, BODY-MASS INDEX, IDENTICAL-TWINS, ACTIVITY QUESTIONNAIRES, FAT DISTRIBUTION, FOOD-INTAKE, 0301 basic medicine, Cancer Research, Medicin och hälsovetenskap, Offita, Physiology, FTO gene, Genome-wide association studies, Medical and Health Sciences, Mathematical and Statistical Techniques, Waist–hip ratio, Medicine and Health Sciences, Genetics (clinical), Public Health, Global Health, Social Medicine and Epidemiology, Physiological Parameters, Female, Genomic Signal Processing, Life Sciences & Biomedicine, Research Article, Signal Transduction, lcsh:QH426-470, Biology, Research and Analysis Methods, Hreyfing (heilsurækt), Journal Article, Erfðafræði, Genetic Predisposition to Disease, Obesity, Waist-Hip Ratio, Body Weight, Human Genetics, Cell Biology, Rannsóknir, Genome Analysis, lcsh:Genetics, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 3111 Biomedicine, Genome-Wide Association Study
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery., The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Funding for this study was provided by the Aase and Ejner Danielsens Foundation; Academy of Finland (102318; 104781, 120315, 123885, 129619, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 250207, 258753, 41071, 77299, 124243, 1114194, 24300796); Accare Center for Child and Adolescent Psychiatry; Action on Hearing Loss (G51); Agence Nationale de la Recherche; Agency for Health Care Policy Research (HS06516); Age UK Research into Ageing Fund; Åke Wiberg Foundation; ALF/LUA Research Grant in Gothenburg; ALFEDIAM; ALK-Abello´ A/S (Hørsholm, Denmark); American Heart Association (13POST16500011, 10SDG269004); Ardix Medical; Arthritis Research UK; Association Diabète Risque Vasculaire; AstraZeneca; Australian Associated Brewers; Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498); Avera Research Institute; Bayer Diagnostics; Becton Dickinson; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); Biocentrum Helsinki; Boston Obesity Nutrition Research Center (DK46200); British Heart Foundation (RG/10/12/28456, SP/04/002); Canada Foundation for Innovation; Canadian Institutes of Health Research (FRN-CCT-83028); Cancer Research UK; Cardionics; Center for Medical Systems Biology; Center of Excellence in Complex Disease Genetics and SALVECenter of Excellence in Genomics (EXCEGEN); Chief Scientist Office of the Scottish Government; City of Kuopio; Cohortes Santé TGIR; Contrat de Projets État-Région; Croatian Science Foundation (8875); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research (DFF–1333-00124, DFF–1331-007308); Danish Diabetes Academy; Danish Medical Research Council; Department of Psychology and Education of the VU University Amsterdam; Diabetes Hilfs- und Forschungsfonds Deutschland; Dutch Brain Foundation; Dutch Ministry of Justice; Emil Aaltonen Foundation; Erasmus Medical Center; Erasmus University; Estonian Government (IUT20-60, IUT24-6); Estonian Ministry of Education and Research (3.2.0304.11-0312); European Commission (230374, 284167, 323195, 692145, FP7 EurHEALTHAgeing-277849, FP7 BBMRI-LPC 313010, nr 602633, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, FP6 LSHM-CT-2004-005272, FP5 QLG2-CT-2002-01254, FP6 LSHG-CT-2006-01947, FP7 HEALTH-F4-2007-201413, FP7 279143, FP7 201668, FP7 305739, FP6 LSHG-CT-2006-018947, HEALTH-F4-2007-201413, QLG1-CT-2001-01252); European Regional Development Fund; European Science Foundation (EuroSTRESS project FP-006, ESF, EU/QLRT-2001-01254); Faculty of Biology and Medicine of Lausanne; Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012, 03IS2061A); Federal State of Mecklenburg - West Pomerania; Fédération Française de Cardiologie; Finnish Cultural Foundation; Finnish Diabetes Association; Finnish Foundation of Cardiovascular Research; Finnish Heart Association; Food Standards Agency; Fondation de France; Fonds Santé; Genetic Association Information Network of the Foundation for the National Institutes of Health; German Diabetes Association; German Federal Ministry of Education and Research (BMBF, 01ER1206, 01ER1507); German Research Council (SFB-1052, SPP 1629 TO 718/2-1); GlaxoSmithKline; Göran Gustafssons Foundation; Göteborg Medical Society; Health and Safety Executive; Heart Foundation of Northern Sweden; Icelandic Heart Association; Icelandic Parliament; Imperial College Healthcare NHS Trust; INSERM, Réseaux en Santé Publique, Interactions entre les déterminants de la santé; Interreg IV Oberrhein Program (A28); Italian Ministry of Economy and Finance; Italian Ministry of Health (ICS110.1/RF97.71); John D and Catherine T MacArthur Foundation; Juho Vainio Foundation; King's College London; Kjell och Märta Beijers Foundation; Kuopio University Hospital; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001); Leiden University Medical Center; Lilly; LMUinnovativ; Lundbeck Foundation; Lundberg Foundation; Medical Research Council of Canada; MEKOS Laboratories (Denmark); Merck Santé; Mid-Atlantic Nutrition Obesity Research Center (P30 DK72488); Ministère de l’Économie, de l’Innovation et des Exportations; Ministry for Health, Welfare and Sports of the Netherlands; Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania; Ministry of Education and Culture of Finland (627;2004-2011); Ministry of Education, Culture and Science of the Netherlands; MRC Human Genetics Unit; MRC-GlaxoSmithKline Pilot Programme Grant (G0701863); Municipality of Rotterdam; Netherlands Bioinformatics Centre (2008.024); Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Genomics Initiative; Netherlands Organisation for Health Research and Development (904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192); Netherlands Organisation for Health Research and Development (2010/31471/ZONMW); Netherlands Organisation for Scientific Research (10-000-1002, GB-MW 940-38-011, 100-001-004, 60-60600-97-118, 261-98-710, GB-MaGW 480-01-006, GB-MaGW 480-07-001, GB-MaGW 452-04-314, GB-MaGW 452-06-004, 175.010.2003.005, 175.010.2005.011, 481-08-013, 480-05-003, 911-03-012); Neuroscience Campus Amsterdam; NHS Foundation Trust; Novartis Pharmaceuticals; Novo Nordisk; Office National Interprofessionel des Vins; Paavo Nurmi Foundation; Påhlssons Foundation; Päivikki and Sakari Sohlberg Foundation; Pierre Fabre; Republic of Croatia Ministry of Science, Education and Sport (108-1080315-0302); Research Centre for Prevention and Health, the Capital Region for Denmark; Research Institute for Diseases in the Elderly (014-93-015, RIDE2); Roche; Russian Foundation for Basic Research (NWO-RFBR 047.017.043); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Sanofi-Aventis; Scottish Executive Health Department (CZD/16/6); Siemens Healthcare; Social Insurance Institution of Finland (4/26/2010); Social Ministry of the Federal State of Mecklenburg-West Pomerania; Société Francophone du Diabète; State of Bavaria; Stroke Association; Swedish Diabetes Association; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20140543); Swedish Research Council (2015-03657); Swedish Medical Research Council (K2007-66X-20270-01-3, 2011-2354); Swedish Society for Medical Research; Swiss National Science Foundation (33CSCO-122661, 33CS30-139468, 33CS30-148401); Tampere Tuberculosis Foundation; The Marcus Borgström Foundation; The Royal Society; The Wellcome Trust (084723/Z/08/Z, 088869/B/09/Z); Timber Merchant Vilhelm Bangs Foundation; Topcon; Torsten and Ragnar Söderberg's Foundation; UK Department of Health; UK Diabetes Association; UK Medical Research Council (MC_U106179471, G0500539, G0600705, G0601966, G0700931, G1002319, K013351, MC_UU_12019/1); UK National Institute for Health Research BioResource Clinical Research Facility and Biomedical Research Centre; UK National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; UK National Institute for Health Research (RP-PG-0407-10371); Umeå University Career Development Award; United States – Israel Binational Science Foundation Grant (2011036); University Hospital Oulu (75617); University Medical Center Groningen; University of Tartu (SP1GVARENG); National Institutes of Health (AG13196, CA047988, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSC271201100004C, HHSN268200900041C, HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268201500001I, HL36310, HG002651, HL034594, HL054457, HL054481, HL071981, HL084729, HL119443, HL126024, N01-AG12100, N01-AG12109, N01-HC25195, N01-HC55015, N01-HC55016, N01-HC55018, N01-HC55019, N01-HC55020, N01-HC55021, N01-HC55022, N01-HD95159, N01-HD95160, N01-HD95161, N01-HD95162, N01-HD95163, N01-HD95164, N01-HD95165, N01-HD95166, N01-HD95167, N01-HD95168, N01-HD95169, N01-HG65403, N02-HL64278, R01-HD057194, R01-HL087641, R01-HL59367, R01HL-086694, R01-HL088451, R24-HD050924, U01-HG-004402, HHSN268200625226C, UL1-RR025005, UL1-RR025005, UL1-TR-001079, UL1-TR-00040, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, DA12854, MH081802, MH66206, R01-D004215701A, R01-DK075787, R01-DK089256, R01-DK8925601, R01-HL088451, R01-HL117078, R01-DK062370, R01-DK072193, DK091718, DK100383, DK078616, 1Z01-HG000024, HL087660, HL100245, R01DK089256, 2T32HL007055-36, U01-HL072515-06, U01-HL84756, NIA-U01AG009740, RC2-AG036495, RC4-AG039029, R03 AG046389, 263-MA-410953, 263-MD-9164, 263-MD-821336, U01-HG004802, R37CA54281, R01CA63, P01CA33619, U01-CA136792, U01-CA98758, RC2-MH089951, MH085520, R01-D0042157-01A, MH081802, 1RC2-MH089951, 1RC2-MH089995, 1RL1MH08326801, U01-HG007376, 5R01-HL08767902, 5R01MH63706:02, HG004790, N01-WH22110, U01-HG007033, UM1CA182913, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221); USDA National Institute of Food and Agriculture (2007-35205-17883); Västra Götaland Foundation; Velux Foundation; Veterans Affairs (1 IK2 BX001823); Vleugels Foundation; VU University’s Institute for Health and Care Research (EMGO+, HEALTH-F4-2007-201413) and Neuroscience Campus Amsterdam; Wellcome Trust (090532, 091551, 098051, 098381); Wissenschaftsoffensive TMO; and Yrjö Jahnsson Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2017
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50. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation

Author: Petra Zeisberger, Patrizia Jensen, Sibylle Cocciardi, Lars Bullinger, Adriana Przybylla, Anne Flörcken, Jeroen Krijgsveld, Andreas Trumpp, Bernhard Radlwimmer, Gerhard Ehninger, Stefan Fröhling, Mattia Falcone, Carl Herrmann, Lital Adler, Patrick Wuchter, Jenny Hansson, Yannic Nonnenmacher, Gernot Poschet, Peter Lichter, Jörg Westermann, Anthony D. Ho, Martje Tönjes, Christoph Lutz, Rüdiger Hell, Carsten Bahr, Wei Wang, Andrea Barnert, Simon Raffel, Claudia Scholl, Ayelet Erez, Niclas Kneisel, Markus Sohn, Christian Thiede, and Karsten Hiller
Subjects: 0301 basic medicine, Proteomics, Mutant, Chromosomal translocation, Protein degradation, Biology, Dioxygenases, Hypoxia-Inducible Factor-Proline Dioxygenases, 03 medical and health sciences, Mice, hemic and lymphatic diseases, Proto-Oncogene Proteins, Animals, Humans, Molecular Targeted Therapy, Transaminases, Epigenomics, Cell Proliferation, Gene knockdown, Multidisciplinary, Epistasis, Genetic, DNA Methylation, Hypoxia-Inducible Factor 1, alpha Subunit, Prognosis, Molecular biology, Isocitrate Dehydrogenase, DNA-Binding Proteins, Leukemia, Myeloid, Acute, 030104 developmental biology, Isocitrate dehydrogenase, DNA methylation, Mutation, Proteolysis, Neoplastic Stem Cells, Ketoglutaric Acids, Female, Stem cell, Amino Acids, Branched-Chain
Abstract: The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mut AML. Gene sets characteristic for IDHmut AML were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1high AML showed robust enrichment for leukaemia stem-cell signatures, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA-BCAT1-αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML.
Published: 2017

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