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1. Genetic Variants in WNT16 and PKD2L1 Locus Affect Heel Ultrasound Bone Stiffness: Analyses from the General Population and Patients Evaluated for Osteoporosis.

Author

Kragl, Angelique, Hannemann, Anke, Nauck, Matthias, Völker, Uwe, Siggelkow, Heide, Teumer, Alexander, and Tzvetkov, Mladen V.

Subjects
HEEL bone, GENETIC variation, BONE density, BONE densitometry, SINGLE nucleotide polymorphisms, OSTEOPOROSIS, GENOME-wide association studies
Abstract

Osteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity. [ABSTRACT FROM AUTHOR]

Published
2023
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2. 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

3. Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank.

Author

Wuttke, Matthias, König, Eva, Katsara, Maria-Alexandra, Kirsten, Holger, Farahani, Saeed Khomeijani, Teumer, Alexander, Li, Yong, Lang, Martin, Göcmen, Burulca, Pattaro, Cristian, Günzel, Dorothee, Köttgen, Anna, and Fuchsberger, Christian

Subjects
KIDNEY physiology, KIDNEY diseases, GENOME-wide association studies, GENETIC variation, BOOSTING algorithms, GENES
Abstract

Genome-wide association studies have discovered hundreds of associations between common genotypes and kidney function but cannot comprehensively investigate rare coding variants. Here, we apply a genotype imputation approach to whole exome sequencing data from the UK Biobank to increase sample size from 166,891 to 408,511. We detect 158 rare variants and 105 genes significantly associated with one or more of five kidney function traits, including genes not previously linked to kidney disease in humans. The imputation-powered findings derive support from clinical record-based kidney disease information, such as for a previously unreported splice allele in PKD2, and from functional studies of a previously unreported frameshift allele in CLDN10. This cost-efficient approach boosts statistical power to detect and characterize both known and novel disease susceptibility variants and genes, can be generalized to larger future studies, and generates a comprehensive resource (https://ckdgen-ukbb.gm.eurac.edu/) to direct experimental and clinical studies of kidney disease. An exome wide association study of UK Biobank data revealed 158 variants and 105 genes significantly associated with kidney function traits and disease. The findings are supported by functional evidence for a previously unreported mutation in CLDN10. [ABSTRACT FROM AUTHOR]

Published
2023
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4. OTTERS: a powerful TWAS framework leveraging summary-level reference data.

Author

Dai, Qile, Zhou, Geyu, Zhao, Hongyu, Võsa, Urmo, Franke, Lude, Battle, Alexis, Teumer, Alexander, Lehtimäki, Terho, Raitakari, Olli T., Esko, Tõnu, eQTLGen Consortium, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Beutner, Frank, Jan Bonder, Marc, and Boomsma, Dorret I.

Subjects
DISEASE risk factors, MONOGENIC & polygenic inheritance (Genetics), OTTERS, SAMPLE size (Statistics)
Abstract

Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies. Here, the authors present a TWAS framework OTTERS that adapts multiple polygenic risk score methods to estimate eQTL weights from summary-level eQTL data. Both simulation and real studies show OTTERS is powerful across a wide range of genetic architectures. [ABSTRACT FROM AUTHOR]

Published
2023
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5. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjornsson, Gardar, Fatemifar, Ghazaleh, Hedman, Asa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Arnlov, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Doerr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engstrom, Gunnar, Esko, Tonu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Gudbjartsson, Daniel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Kober, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, Maerz, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Voelker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, Lumbers, R Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M, Habegger, Lukas, Hahn, Young, Hawes, Alicia, van Hout, Cristopher, Jones, Marcus B, Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K, McCarthy, Shane, Mitnaul, Lyndon J, O'Dushlaine, Colm, Overton, John D, Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G, Schleicher, Thomas D, Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C, Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H, Widom, Louis, Wolf, Sarah E, Yadav, Ashish, Ye, Bin, Ctr, Regeneron Genetics, Shah, Sonia [0000-0001-5860-4526], Henry, Albert [0000-0001-7422-2288], Roselli, Carolina [0000-0001-5267-6756], Lin, Honghuang [0000-0003-3043-3942], Chaffin, Mark D. [0000-0002-1234-5562], Helgadottir, Anna [0000-0002-1806-2467], Verweij, Niek [0000-0002-4303-7685], Almgren, Peter [0000-0002-0473-0241], Chen, Xu [0000-0002-7299-3238], Ghanbari, Mohsen [0000-0002-9476-7143], Giedraitis, Vilmantas [0000-0003-3423-2021], Gross, Stefan [0000-0003-4121-7161], Guðbjartsson, Daníel F. [0000-0002-5222-9857], Hyde, Craig L. [0000-0002-6939-287X], Ingelsson, Erik [0000-0003-2256-6972], Jukema, J. Wouter [0000-0002-3246-8359], Kleber, Marcus E. [0000-0003-0663-7275], Koekemoer, Andrea [0000-0001-8222-3547], Langenberg, Claudia [0000-0002-5017-7344], Lindgren, Cecilia M. [0000-0002-4903-9374], Lovering, Ruth C. [0000-0002-9791-0064], Luan, Jian’an [0000-0003-3137-6337], Magnusson, Patrik [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mordi, Ify R. [0000-0002-2686-729X], Morris, Andrew D. [0000-0002-1766-0473], Nagle, Michael W. [0000-0002-4677-7582], Nelson, Christopher P. [0000-0001-8025-2897], Palmer, Colin N. A. [0000-0002-6415-6560], Rice, Kenneth M. [0000-0002-3071-7278], Rotter, Jerome I. [0000-0001-7191-1723], Salomaa, Veikko [0000-0001-7563-5324], van Setten, Jessica [0000-0002-4934-7510], Svensson, Per [0000-0003-0372-6272], Taylor, Kent D. [0000-0002-2756-4370], Teder-Laving, Maris [0000-0002-5872-1850], Teumer, Alexander [0000-0002-8309-094X], Tyl, Benoit [0000-0001-5297-8412], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Wiggins, Kerri L. [0000-0003-2749-1279], Hemingway, Harry [0000-0003-2279-0624], Yang, Jian [0000-0003-2001-2474], Visscher, Peter M. [0000-0002-2143-8760], Lubitz, Steven A. [0000-0002-9599-4866], Sattar, Naveed [0000-0002-1604-2593], Cappola, Thomas P. [0000-0002-9630-7204], Asselbergs, Folkert W. [0000-0002-1692-8669], Kuchenbaecker, Karoline [0000-0001-9726-603X], Ellinor, Patrick T. [0000-0002-2067-0533], Vasan, Ramachandran S. [0000-0001-7357-5970], Lumbers, R. Thomas [0000-0002-9077-4741], Apollo - University of Cambridge Repository, Chaffin, Mark D [0000-0002-1234-5562], Guðbjartsson, Daníel F [0000-0002-5222-9857], Hyde, Craig L [0000-0002-6939-287X], Jukema, J Wouter [0000-0002-3246-8359], Kleber, Marcus E [0000-0003-0663-7275], Lindgren, Cecilia M [0000-0002-4903-9374], Lovering, Ruth C [0000-0002-9791-0064], Luan, Jian'an [0000-0003-3137-6337], Mordi, Ify R [0000-0002-2686-729X], Morris, Andrew D [0000-0002-1766-0473], Nagle, Michael W [0000-0002-4677-7582], Nelson, Christopher P [0000-0001-8025-2897], Palmer, Colin NA [0000-0002-6415-6560], Rice, Kenneth M [0000-0002-3071-7278], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, Andre G [0000-0002-7276-3387], Wiggins, Kerri L [0000-0003-2749-1279], Visscher, Peter M [0000-0002-2143-8760], Lubitz, Steven A [0000-0002-9599-4866], Cappola, Thomas P [0000-0002-9630-7204], Asselbergs, Folkert W [0000-0002-1692-8669], Ellinor, Patrick T [0000-0002-2067-0533], Vasan, Ramachandran S [0000-0001-7357-5970], Lumbers, R Thomas [0000-0002-9077-4741], Palmer, Colin N A [0000-0002-6415-6560], Cardiovascular Centre (CVC), University of Queensland [Brisbane], University College of London [London] (UCL), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University Medical Center Groningen [Groningen] (UMCG), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), deCODE genetics [Reykjavik], Karolinska Institutet [Stockholm], Pfizer, University of Pennsylvania [Philadelphia], University of Groningen [Groningen], Imperial College London, Lund University [Lund], Herlev and Gentofte Hospital, Massachusetts General Hospital [Boston], Department of Neurobiology, Care Sciences and Society [Stockholm, Sweden] (Division of Family Medicine), Dalarna University, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, Department of Biostatistics, University of Washington [Seattle], Emory University School of Medicine, Emory University [Atlanta, GA], The University of Texas Medical School at Houston, Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, Novartis Institutes for BioMedical Research (NIBR), University of Liverpool, Universität Heidelberg [Heidelberg], Medizinische Fakultät Mannheim, The Alan Turing Institute, Ninewells Hospital and Medical School [Dundee], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Minnesota System, Regeneron Pharmaceuticals [Tarrytown], Department of Clinical Sciences, Cardiovascular Epidemiology, Skane University Hospital [Lund], Institute of Genomics [Tartu, Estonia], University of Tartu, Robertson Centre for Biostatistics, University of Glasgow, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Uppsala University, Brigham & Women’s Hospital [Boston] (BWH), University of Maryland School of Medicine, University of Maryland System, School of Science and Engineering (Reykjavik University), Carver College of Medicine, University of Iowa, Geisinger Health System [Danville, PA, USA], Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, Uppsala Universitet [Uppsala], Leiden University Medical Center (LUMC), Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Glenfield Hospital, University Hospitals Leicester, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Big Data Institute, University of Oxford [Oxford], University of Iowa [Iowa City], The Wellcome Trust Centre for Human Genetics [Oxford], Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Medical University Graz, Skane University Hospital [Malmo], Vanderbilt University School of Medicine [Nashville], University of Edinburgh, Université médicale de Vienne, Autriche, National Institute for Health and Welfare [Helsinki], University of Turku, Birmingham Women's and Children's NHS Foundation Trust, Kaiser Permanente, Harbor UCLA Medical Center [Torrance, Ca.], Los Angeles Biomedical Research Institute (LA BioMed), University Medical Center [Utrecht], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Seattle Epidemiologic Research and Information Center [Seattle], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Department of Cardiology, Södersjukhuset, Stockholm, Estonian Genome and Medicine, Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], Aalborg University [Denmark] (AAU), Institut de Recherches SERVIER (IRS), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, GlaxoSmithKline, Glaxo Smith Kline, Northeastern Ohio Medical University (NEOMED), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Department of Cardiovascular Sciences [Leicester], University of Leicester, Queensland Brain Institute, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, University of Dundee, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Atherosclerosis Risk in Communities Study (ARIC)The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694 and RC2 HL102419, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT- CHF)This project was funded by a grant from the European Commission (FP7‐242209‐ BIOSTAT‐CHF, EudraCT 2010–020808–29). Cardiovascular Health Study (CHS) This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Heart Failure Study (deCODE) We at deCODE thank the women and men of Iceland that have participated in our studies and our colleagues that contributed to data collection and processing. DiscovEHR We acknowledge and thank all participants in Geisinger’s MyCode Community Health Initiative for their support and permission to use their health and genomic information in the DiscovEHR collaboration. This work was supported by the Regeneron Genetics Center and Geisinger. Estonian Genome Center at the University of Tartu (EGCUT) This study was supported by Estonian Research Council Grant IUT20-60, EU, H2020 grant 692145, European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) GENTRANSMED. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) The EPHESUS was supported by Pfizer, Inc. The European Prospective Investigation of Cancer, Norfolk study (EPIC-Norfolk) The EPIC-Norfolk Study is supported by programme grants from the Medical Research Council UK (G1000143) and Cancer Research UK (C864/A14136) and with additional support from the European Union, Stroke Association, British Heart Foundation, Research into Ageing, Department of Health, The Wellcome Trust and the Food Standards Agency. NJW and CL also acknowledge support from the Medical Research Council, UK (MC_UU_12015/1, MC_PC_13048). We thank all EPIC participants and staff for their contribution to the study, and thank staff from the Technical, Field Epidemiology and Data Functional Group Teams of the Medical Research Council Epidemiology Unit in Cambridge, UK, for carrying out sample preparation, DNA provision and quality control, genotyping and data handling work. Framingham Heart Study (FHS) This work was conducted using data and resources from the Framingham Heart Study (FHS) of the National Heart Lung and Blood Institute and Boston University School of Medicine. The study was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No.N02-HL-6-4278). The work was also supported by R01 HL093328, R01 HL105993, and R01 HL71039 (PI: Ramachandran). FINRISK V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Genetics of Diabetes Audit and Research Tayside Scotland GoDARTS) The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. We acknowledge the support of the Health Informatics Centre, University of Dundee, for managing and supplying the anonymized data and NHS Tayside, the original data owner. The Genetic Risk Assessment of Defibrillator Events (GRADE) NIH-NHLBI R01 HL77398 (Genetic Modulators of Sudden Death). S.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study We extend our appreciation to the participants of the LURIC study, without their collaboration, this article would not have been written. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. LURIC has received funding from the 7th Framework Program (RiskyCAD, grant agreement number 305739 and Atheroremo, grant agreement number 201668) of the European Union. Malmö Diet and Cancer Study (MDCS) J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016- 0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15- 0067) to the Lund University Diabetes Center. The Malmo Diet and Cancer Study was made possible by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, and the Malmo city council. Penn Heart Failure Study (PHFS) The study was supported by NIH grants (NIH R01L088577 and NIH R01H105993). Prevention of REnal and Vascular ENd-stage Disease (PREVEND) The Prevention of Renal and Vascular Endstage Disease Study (PREVEND) genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), the Netherlands organisation for health research and development (NWO VENI grant 916.761.70), and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Niek Verweij was supported by NWO VENI grant 016.186.125. PROspective Study of Pravastatin in the Elderly at Risk for vascular disease (PROSPER)The PROSPER study was supported by an investigator-initiated grant obtained from Bristol- Myers Squibb. Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Study of Health in Pomerania (SHIP) SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID)SOLID-TIMI 52 was funded by GlaxoSmithKline. TwinGene (TwinGene) TwinGene received funding from the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254, QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF) and the Heart and Lung foundation no. 20070481. TwinGene is part of the Swedish Twin Registry which is managed by Karolinska Institutet and receives funding through the Swedish Research Council (2017–00641). UK Biobank (UKBiobank) This research has been conducted using the UK Biobank Resource under Application Number 15422. This work was supported in part by grants to R.T.L. from the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074, MRC Proximity to Discovery Award Scheme, the American Heart Association Institute for Precision Mecidine, Pfizer Ltd, the University College London British Heart Foundation Research Accelerator (AA/18/6/34223), and was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A. H. is supported by the British Heart Foundation Cardiovascular Biomedicine PhD studentship. R.T.L is supported by a UK Research and Innovation Rutherford Fellowship and was previously supported by a National Institutes of Health Research Clinical Lectureship. Uppsala Longitudinal Study of Adult Men (ULSAM) J.Ä. is supported by the Swedish Research Council and the Swedish Heart Lung foundation. C.M.L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138- 27). Women’s Genome Health Study (WGHS) The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467, HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen., Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, Dánartíðni, Epidemiology, LOCI, 45/43, General Physics and Astronomy, Muscle Proteins, Genome-wide association study, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, DISEASE, Ventricular Function, Left, Coronary artery disease, 0302 clinical medicine, Risk Factors, Atrial Fibrillation, IMPUTATION, Medicine, Blóðrásarsjúkdómar, 692/308/174, lcsh:Science, 2. Zero hunger, RISK, Multidisciplinary, Microfilament Proteins, article, Atrial fibrillation, Mendelian Randomization Analysis, CATALOG, 3. Good health, OBESITY, Erfðarannsóknir, Cardiomyopathies, Medical Genetics, Cyclin-Dependent Kinase Inhibitor p21, Science, 631/208/205/2138, Heart failure, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 631/443/592/2727, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, RESOURCE, Humans, Mortality, METAANALYSIS, Genetic association, Medicinsk genetik, Adaptor Proteins, Signal Transducing, Heart Failure, HYPERTENSION, business.industry, Case-control study, Klinisk medicin, 692/699/75/230, General Chemistry, Cardiovascular genetics, medicine.disease, R1, 030104 developmental biology, Case-Control Studies, lcsh:Q, Morbidity, Clinical Medicine, business, Apoptosis Regulatory Proteins, Carrier Proteins, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies., We acknowledge the contribution from the EchoGen Consortium.

Published
2020

6. Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities.

Author

Francis, Catherine M., Futschik, Matthias E., Huang, Jian, Bai, Wenjia, Sargurupremraj, Muralidharan, Teumer, Alexander, Breteler, Monique M. B., Petretto, Enrico, Ho, Amanda S. R., Amouyel, Philippe, Engelter, Stefan T., Bülow, Robin, Völker, Uwe, Völzke, Henry, Dörr, Marcus, Imtiaz, Mohammed-Aslam, Aziz, N. Ahmad, Lohner, Valerie, Ware, James S., and Debette, Stephanie

Subjects
THORACIC aorta, WHITE matter (Nerve tissue), AORTIC aneurysms, GENOME-wide association studies, CARDIAC magnetic resonance imaging, AORTA, SMOOTH muscle contraction
Abstract

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease. Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease. [ABSTRACT FROM AUTHOR]

Published
2022
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7. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, University of Oslo, Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Bragi Walters, G., Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Modenato, Claudia, Monereo Sánchez, Jennifer, Morris, Derek W., Mühleisen, Thomas W., Pausova, Zdenka, Olde Loohuis, Loes M., Peralta, Juan M., Pike, G. Bruce, Prieto, Carlos, Quinlan, Erin B., Wright, Margaret J., Reinbold, Céline S., Stefansson, Hreinn, Reis Marques, Tiago, Bernard, Manon, Rucker, James J. H., Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Agartz, Ingrid, Shin, Jean, Shumskaya, Elena, Stefansson, Kari, Silva, Ana I., Sisodiya, Sanjay M., Blackburn, Nicholas B., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Djurovic, Srdjan, Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Jacquemont, Sébastien, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., Blangero, John, van't Ent, Dennis, van den Bree, Marianne B. M., Westlye, Lars T., Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Thompson, Paul M., Boomsma, Dorret I., Andreassen, Ole A., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Groenewold, Nynke A., Cahn, Wiepke, Hashimoto, Ryota, Calhoun, Vincent, Caspers, Svenja, Ching, Christopher R. K., Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Gústafsson, Ómar, Dalvie, Shareefa, Dazzan, Paola, Hehir-Kwa, Jayne Y., de Geus, de Geus, Zubicaray, Greig I. de, de Zwarte, Sonja M. C., Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Haavik, Jan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Hibar, Derrek P., Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Haberg, Asta K., Gareau, Thomas, Ge,Tian, Glahn, David C., Grabe, Hans-Jörgen, Hillegers, Manon H. J., Hall, Jeremy, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Murray, Robin M., Hulshoff Pol, Hilleke E., Ophoff, Roel A., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E. M., Nielsen, Jacob, Kumar, Kuldeep, Le Hellard, Stephanie, Owen, Michael J., Leu, Costin, Linden, David E. J., Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Nordvik, Jan E., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., Paus, Tomas, McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, Nyberg, Lars, Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, University of Oslo, Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Bragi Walters, G., Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Modenato, Claudia, Monereo Sánchez, Jennifer, Morris, Derek W., Mühleisen, Thomas W., Pausova, Zdenka, Olde Loohuis, Loes M., Peralta, Juan M., Pike, G. Bruce, Prieto, Carlos, Quinlan, Erin B., Wright, Margaret J., Reinbold, Céline S., Stefansson, Hreinn, Reis Marques, Tiago, Bernard, Manon, Rucker, James J. H., Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Agartz, Ingrid, Shin, Jean, Shumskaya, Elena, Stefansson, Kari, Silva, Ana I., Sisodiya, Sanjay M., Blackburn, Nicholas B., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Djurovic, Srdjan, Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Jacquemont, Sébastien, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., Blangero, John, van't Ent, Dennis, van den Bree, Marianne B. M., Westlye, Lars T., Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Thompson, Paul M., Boomsma, Dorret I., Andreassen, Ole A., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Groenewold, Nynke A., Cahn, Wiepke, Hashimoto, Ryota, Calhoun, Vincent, Caspers, Svenja, Ching, Christopher R. K., Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Gústafsson, Ómar, Dalvie, Shareefa, Dazzan, Paola, Hehir-Kwa, Jayne Y., de Geus, de Geus, Zubicaray, Greig I. de, de Zwarte, Sonja M. C., Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Haavik, Jan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Hibar, Derrek P., Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Haberg, Asta K., Gareau, Thomas, Ge,Tian, Glahn, David C., Grabe, Hans-Jörgen, Hillegers, Manon H. J., Hall, Jeremy, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Murray, Robin M., Hulshoff Pol, Hilleke E., Ophoff, Roel A., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E. M., Nielsen, Jacob, Kumar, Kuldeep, Le Hellard, Stephanie, Owen, Michael J., Leu, Costin, Linden, David E. J., Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Nordvik, Jan E., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., Paus, Tomas, McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, and Nyberg, Lars

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021

8. Effects of Apolipoprotein E polymorphism on carotid intima-media thickness, incident myocardial infarction and incident stroke.

Author

Pitchika, Anitha, Markus, Marcello Ricardo Paulista, Schipf, Sabine, Teumer, Alexander, Van der Auwera, Sandra, Nauck, Matthias, Dörr, Marcus, Felix, Stephan, Grabe, Hans-Jörgen, Völzke, Henry, and Ittermann, Till

Subjects
CAROTID intima-media thickness, APOLIPOPROTEIN E, MYOCARDIAL infarction, ATHEROSCLEROTIC plaque, CAROTID artery, GENETIC polymorphisms
Abstract

The Apolipoprotein E (APOE) gene polymorphism (rs429358 and rs7412) shows a well-established association with lipid profiles, but its effect on cardiovascular disease is still conflicting. Therefore, we examined the association of different APOE alleles with common carotid artery intima-media thickness (CCA-IMT), carotid plaques, incident myocardial infarction (MI) and stroke. We analyzed data from 3327 participants aged 20–79 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 14.5 years. Linear, logistic, and Cox-regression models were used to assess the associations of the APOE polymorphism with CCA-IMT, carotid plaques, incident MI and stroke, respectively. In our study, the APOE E2 allele was associated with lower CCA-IMT at baseline compared to E3 homozygotes (β: − 0.02 [95% CI − 0.04, − 0.004]). Over the follow-up, 244 MI events and 218 stroke events were observed. APOE E2 and E4 allele were not associated with incident MI (E2 HR: 1.06 [95% CI 0.68, 1.66]; E4 HR: 1.03 [95% CI 0.73, 1.45]) and incident stroke (E2 HR: 0.79 [95% CI 0.48, 1.30]; E4 HR: 0.96 [95% CI 0.66, 1.38]) in any of the models adjusting for potential confounders. However, the positive association between CCA-IMT and incident MI was more pronounced in E2 carriers than E3 homozygotes. Thus, our study suggests that while APOE E2 allele may predispose individuals to lower CCA-IMT, E2 carriers may be more prone to MI than E3 homozygotes as the CCA-IMT increases. APOE E4 allele had no effect on CCA-IMT, plaques, MI or stroke. [ABSTRACT FROM AUTHOR]

Published
2022
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9. Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Author

Portilla-Fernández, Eliana, Hwang, Shih-Jen, Wilson, Rory, Maddock, Jane, Hill, W. David, Teumer, Alexander, Mishra, Pashupati P., Brody, Jennifer A., Joehanes, Roby, Ligthart, Symen, Ghanbari, Mohsen, Kavousi, Maryam, Roks, Anton J. M., Danser, A. H. Jan, Levy, Daniel, Peters, Annette, Ghasemi, Sahar, Schminke, Ulf, Dörr, Marcus, and Grabe, Hans J.

Subjects
CAROTID intima-media thickness, CORONARY artery disease, CARDIOVASCULAR diseases risk factors, ARYL hydrocarbon receptors, ISCHEMIC stroke, DNA methyltransferases
Abstract

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = −0.0264, p value = 3.5 × 10–8) in the discovery panel and was replicated in replication panel (beta = −0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease. [ABSTRACT FROM AUTHOR]

Published
2021
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10. Physical activity, sedentary behavior and risk of coronary artery disease, myocardial infarction and ischemic stroke: a two-sample Mendelian randomization study.

Author

Bahls, Martin, Leitzmann, Michael F., Karch, André, Teumer, Alexander, Dörr, Marcus, Felix, Stephan B., Meisinger, Christa, Baumeister, Sebastian E., and Baurecht, Hansjörg

Abstract

Aims: Observational evidence suggests that physical activity (PA) is inversely and sedentarism positively related with cardiovascular disease risk. We performed a two-sample Mendelian randomization (MR) analysis to examine whether genetically predicted PA and sedentary behavior are related to coronary artery disease, myocardial infarction, and ischemic stroke. Methods and results: We used single nucleotide polymorphisms (SNPs) associated with self-reported moderate to vigorous PA (n = 17), accelerometer based PA (n = 7) and accelerometer fraction of accelerations > 425 milli-gravities (n = 7) as well as sedentary behavior (n = 6) in the UK Biobank as instrumental variables in a two sample MR approach to assess whether these exposures are related to coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D genome-wide association study (GWAS) or ischemic stroke in the MEGASTROKE GWAS. The study population included 42,096 cases of coronary artery disease (99,121 controls), 27,509 cases of myocardial infarction (99,121 controls), and 34,217 cases of ischemic stroke (404,630 controls). We found no associations between genetically predicted self-reported moderate to vigorous PA, accelerometer-based PA or accelerometer fraction of accelerations > 425 milli-gravities as well as sedentary behavior with coronary artery disease, myocardial infarction, and ischemic stroke. Conclusions: These results do not support a causal relationship between PA and sedentary behavior with risk of coronary artery disease, myocardial infarction, and ischemic stroke. Hence, previous observational studies may have been biased. [ABSTRACT FROM AUTHOR]

Published
2021
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11. Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome.

Author

Porcu, Eleonora, Sadler, Marie C., Lepik, Kaido, Auwerx, Chiara, Wood, Andrew R., Weihs, Antoine, Sleiman, Maroun S. Bou, Ribeiro, Diogo M., Bandinelli, Stefania, Tanaka, Toshiko, Nauck, Matthias, Völker, Uwe, Delaneau, Olivier, Metspalu, Andres, Teumer, Alexander, Frayling, Timothy, Santoni, Federico A., Reymond, Alexandre, and Kutalik, Zoltán

Subjects
TRANSCRIPTOMES, PHENOTYPES, GENES, STATISTICAL correlation, BIOMARKERS, GENE expression
Abstract

Comparing transcript levels between healthy and diseased individuals allows the identification of differentially expressed genes, which may be causes, consequences or mere correlates of the disease under scrutiny. We propose a method to decompose the observational correlation between gene expression and phenotypes driven by confounders, forward- and reverse causal effects. The bi-directional causal effects between gene expression and complex traits are obtained by Mendelian Randomization integrating summary-level data from GWAS and whole-blood eQTLs. Applying this approach to complex traits reveals that forward effects have negligible contribution. For example, BMI- and triglycerides-gene expression correlation coefficients robustly correlate with trait-to-expression causal effects (rBMI = 0.11, PBMI = 2.0 × 10−51 and rTG = 0.13, PTG = 1.1 × 10−68), but not detectably with expression-to-trait effects. Our results demonstrate that studies comparing the transcriptome of diseased and healthy subjects are more prone to reveal disease-induced gene expression changes rather than disease causing ones. Identification of gene expression changes between healthy and diseased individuals can reveal mechanistic insights and biomarkers. Here, the authors propose a bi-directional transcriptome-wide Mendelian Randomization approach to assess causal effects between gene expression and complex traits. [ABSTRACT FROM AUTHOR]

Published
2021
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13. Thyroid function, sex hormones and sexual function: a Mendelian randomization study.

Author

Kjaergaard, Alisa D., Marouli, Eirini, Papadopoulou, Areti, Deloukas, Panos, Kuś, Aleksander, Sterenborg, Rosalie, Teumer, Alexander, Burgess, Stephen, Åsvold, Bjørn O., Chasman, Daniel I., Medici, Marco, and Ellervik, Christina

Subjects
SEX hormones, THYROTROPIN, THYROID gland, MENARCHE, TESTOSTERONE, IMPOTENCE, SEXUAL dysfunction, HYPERTHYROIDISM
Abstract

Hypothyroidism and hyperthyroidism are observationally associated with sex hormone concentrations and sexual dysfunction, but causality is unclear. We investigated whether TSH, fT4, hypo- and hyperthyroidism are causally associated with sex hormones and sexual function. We used publicly available summary statistics from genome-wide association studies on TSH and fT4 and hypo- and hyperthyroidism from the ThyroidOmics Consortium (N ≤ 54,288). Outcomes from UK Biobank (women ≤ 194,174/men ≤ 167,020) and ReproGen (women ≤ 252,514) were sex hormones (sex hormone binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) and sexual function (ovulatory function in women: duration of menstrual period, age at menarche and menopause, reproductive lifespan, and erectile dysfunction in men). We performed two-sample Mendelian randomization (MR) analyses on summary level, and unweighted genetic risk score (GRS) analysis on individual level data. One SD increase in TSH was associated with a 1.332 nmol/L lower (95% CI: − 0.717,− 1.946; p = 2 × 10–5) SHBG and a 0.103 nmol/l lower (− 0.051,V0.154; p = 9 × 10–5) testosterone in two-sample MR, supported by the GRS approach. Genetic predisposition to hypothyroidism was associated with decreased and genetic predisposition to hyperthyroidism with increased SHBG and testosterone in both approaches. The GRS for fT4 was associated with increased testosterone and estradiol in women only. The GRS for TSH and hypothyroidism were associated with increased and the GRS for hyperthyroidism with decreased FAI in men only. While genetically predicted thyroid function was associated with sex hormones, we found no association with sexual function. [ABSTRACT FROM AUTHOR]

Published
2021
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14. Hair cortisol in twins:heritability and genetic overlap with psychological variables and stress-system genes

Author

Rietschel, Liz, Streit, Fabian, McGrath, John, Davies, Gareth, Davies, Gail, de Geus, Eco J C, De Jager, Philip, Deary, Ian J, Degenhardt, Franziska, Dunn, Erin C, Ehli, Erik A, Eley, Thalia C, Escott-Price, Valentina, Hickie, Ian B, Esko, Tõnu, Finucane, Hilary K, Gill, Michael, Gordon, Scott D, Grove, Jakob, Hall, Lynsey S, Hansen, Thomas F, Søholm Hansen, Christine, Heath, Andrew C, Hansell, Narelle K, Henders, Anjali K, Herms, Stefan, Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke- Jan, Hougaard, David, Huang, Hailiang, Ising, Marcus, Jansen, Rick, Wright, Margaret J, Jorgenson, Eric, Kloiber, Stefan, Knowles, James A, Kretzschmar, Warren W, Krogh, Jesper, Kutalik, Zoltán, Lang, Maren, Lewis, Glyn, Li, Yihan, MacIntyre, Donald J, Gillespie, Nathan A, Madden, Pamela Af, Marchine, Jonathan, Mbarek, Hamdi, McGuffin, Peter, Mehta, Divya, Metspalu, Andres, Middeldorp, Christel M, Mihailov, Evelin, Milani, Lili, Montgomery, Grant W, Forstner, Andreas J, Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nordentoft, Merete, Nyholt, Dale R, O'Donovan, Michael C, O'Reilly, Paul F, Oskarsson, Hogni, Owen, Michael J, Schulze, Thomas G, Paciga, Sara A, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Pedersen, Nancy L, Pergadia, Michele L, Peterson, Roseann E, Pettersson, Erik, Peyrot, Wouter J, Porteous, David J, Posthuma, Danielle, Wüst, Stefan, Potash, James B, Quiroz, Jorge A, Rice, John P, Riley, Brien P, Rivera, Margarita, Ruderfer, Douglas M, Saeed Mirza, Saira, Schoevers, Robert, Shen, Ling, Shi, Jianxin, Nöthen, Markus M, Sigurdsson, Engilbert, Sinnamon, Grant Cb, Smit, Johannes H, Smith, Daniel J, Smoller, Jordan W, Stephansson, Hreinn, Steinberg, Stacy, Strohmaier, Jana, Tansey, Katherine E, Teumer, Alexander, Baumgartner, Markus R, Thompson, Wesley, Thomson, Pippa A, Thorgeirsson, Thorgeir E, Treutlein, Jens, Trzaskowski, Maciej, Umbricht, Daniel, van der Auwera, Sandra, van Grootheest, Gerard, van Hemert, Albert M, Viktorin, Alexander, Zhu, Gu, Walker, Brian R, Völzke, Henry, Wang, Yunpeng, Webb, Bradley T, Weissman, Myrna M, Wellmann, Jürgen, Willemsen, Gonneke, Xi, Hualin S, Baune, Bernhard T, Blackwood, Douglas H R, Boomsma, Dorret I, Crawford, Andrew A, Børglum, Anders D, Buttenschøn, Henriette N, Cichon, Sven, Domenici, Enrico, Flint, Jonathan, Grabe, Hans J, Hamilton, Steven P, Kendler, Kenneth S, Li, Qingqin S, Lucae, Susanne, Colodro-Conde, Lucía, Magnusson, Patrik K, McIntosh, Andrew M, Mors, Ole, Bo Mortensen, Preben, Müller-Myhsok, Bertram, Penninx, Brenda Wjh, Perlis, Roy H, Preisig, Martin, Schaefer, Catherine, Medland, Sarah E, Stephansson, Kari, Tiemeier, Henning, Uher, Rudolf, Werge, Thomas, Winslow, Ashley R, Breen, Gerome, Levinson, Douglas F, Lewis, Cathryn M, Wray, Naomi R, Sullivan, Patrick F, Martin, Nicholas G, Rietschel, Marcella, Bolton, Jennifer L, Hayward, Caroline, Direk, Nese, Anderson, Anna, McAloney, Kerrie, Huffman, Jennifer, Wilson, James F, Campbell, Harry, Rudan, Igor, Wright, Alan, Hastie, Nicholas, Wild, Sarah H, Velders, Fleur P, Hofman, Albert, Uitterlinden, Andre G, Frank, Josef, Lahti, Jari, Räikkönen, Katri, Kajantie, Eero, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Kaakinen, Marika, Järvelin, Marjo-Riitta, Timpson, Nicholas J, Davey Smith, George, Couvy-Duchesne, Baptiste, Ring, Susan M, Evans, David M, St Pourcain, Beate, Tanaka, Toshiko, Milaneschi, Yuri, Bandinelli, Stefania, Ferrucci, Luigi, van der Harst, Pim, Rosmalen, Judith Gm, Bakker, Stephen Jl, Witt, Stephanie H, Verweij, Niek, Dullaart, Robin Pf, Mahajan, Anubha, Lindgren, Cecilia M, Morris, Andrew, Lind, Lars, Ingelsson, Erik, Anderson, Laura N, Pennell, Craig E, Lye, Stephen J, Binz, Tina M, Matthews, Stephen G, Eriksson, Joel, Mellstrom, Dan, Ohlsson, Claes, Price, Jackie F, Strachan, Mark Wj, Reynolds, Rebecca M, Ripke, Stephan, Mattheisen, Manuel, CORtisolNETwork, Abdellaoui, Abdel, Adams, Mark J, Agerbo, Esben, Air, Tracy M, Andlauer, Till Fm, Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan Tf, Bennett, David A, Berger, Klaus, Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics, Bigdeli, Tim B, Bybjerg-Grauholm, Jonas, Byrne, Enda M, Cai, Na, Castelao, Enrique, Clarke, Toni-Kim, Coleman, Jonathan Ri, Consortium, Converge, Craddock, Nick, Dannlowski, Udo, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, Internal medicine, Amsterdam Reproduction & Development (AR&D), Human genetics, APH - Methodology, APH - Digital Health, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Zurich, Rietschel, Liz, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, and APH - Personalized Medicine

Subjects
Male, Oncology, Netherlands Twin Register (NTR), Multifactorial Inheritance, Hydrocortisone, lcsh:Medicine, 340 Law, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Twins, Dizygotic, SOCIOECONOMIC-STATUS, Young adult, lcsh:Science, Child, 610 Medicine & health, Genetics, Multidisciplinary, Depression, PSYCHIATRIC-DISORDERS, 10218 Institute of Legal Medicine, Neuroticism, DEPRESSIVE SYMPTOMS, MORNING CORTISOL, Female, FUTURE-DIRECTIONS, Adult, medicine.medical_specialty, Cortisol awakening response, Adolescent, PERCEIVED STRESS, Biology, Genetic correlation, Article, LONG-TERM CORTISOL, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, Humans, neoplasms, Behavioural genetics, 1000 Multidisciplinary, Models, Genetic, lcsh:R, Twins, Monozygotic, ADRENAL AXIS ACTIVITY, MAJOR DEPRESSION, Heritability, Twin study, R1, digestive system diseases, 030227 psychiatry, ddc:000, INTRAINDIVIDUAL STABILITY, lcsh:Q, Stress, Psychological, 030217 neurology & neurosurgery, Hair
Abstract

Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables. Consortia CORtisolNETwork (CORNET) Consortium Jennifer L. Bolton21 Caroline Hayward23 Nese Direk24,25 Anna Anderson21 Jennifer Huffman23 James F. Wilson26 Harry Campbell26 Igor Rudan26 Alan Wright23 Nicholas Hastie23 Sarah H. Wild26 Fleur P. Velders24 Albert Hofman24 Andre G. Uitterlinden24,27 Jari Lahti28 Katri Räikkönen28 Eero Kajantie29 Elisabeth Widen30 Aarno Palotie30,31 Johan G. Eriksson29,32,33,34,35 Marika Kaakinen36 Marjo-Riitta Järvelin36,37,38,39 Nicholas J. Timpson40 George Davey Smith40 Susan M. Ring41 David M. Evans40 Beate St Pourcain41 Toshiko Tanaka42 Yuri Milaneschi42,43 Stefania Bandinelli44 Luigi Ferrucci42 Pim van der Harst45,46,47 Judith GM Rosmalen48 Stephen JL Bakker49 Niek Verweij45 Robin PF Dullaart49 Anubha Mahajan50 Cecilia M. Lindgren50 Andrew Morris50 Lars Lind51 Erik Ingelsson51 Laura N. Anderson52 Craig E. Pennell53 Stephen J. Lye52 Stephen G. Matthews54 Joel Eriksson55 Dan Mellstrom55 Claes Ohlsson55 Jackie F. Price26 Mark WJ Strachan21 Rebecca M. Reynolds21 Henning Tiemeier24,56,57 Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC) Stephan Ripke58,59,60 Manuel Mattheisen61,62,63 Abdel Abdellaoui64 Mark J. Adams65 Esben Agerbo66,8,67 Tracy M. Air68 Till FM Andlauer69,70 Silviu-Alin Bacanu71 Marie Bækvad-Hansen67,72 Aartjan TF Beekman43 David A. Bennett73 Klaus Berger74 Tim B. Bigdeli71,11 Jonas Bybjerg-Grauholm67,72 Enda M. Byrne5 Na Cai75 Enrique Castelao76 Toni-Kim Clarke65 Jonathan RI Coleman77 Converge Consortium78 Nick Craddock79 Udo Dannlowski80,81 Gareth Davies82 Gail Davies83 Eco. J. C. de Geus64,84 Philip De Jager85 Ian J. Deary83 Franziska Degenhardt12,13 Erin C. Dunn86,87,88 Erik A. Ehli82 Thalia C. Eley77 Valentina Escott-Price89 Tõnu Esko58,90,91,92 Hilary K. Finucane93,94 Michael Gill95 Scott D. Gordon96 Jakob Grove61,62,67,97 Lynsey S. Hall65,98 Thomas F. Hansen99,100 Christine Søholm Hansen67,72 Thomas F. Hansen101 Andrew C. Heath102 Anjali K. Henders5 Stefan Herms12,13,15 Per Hoffmann12,13,15 Georg Homuth103 Carsten Horn104 Jouke- Jan Hottenga64 David Hougaard67,72 Hailiang Huang59,86,105 Marcus Ising106 Rick Jansen43 Eric Jorgenson107 Stefan Kloiber108,109 James A Knowles110 Warren W. Kretzschmar50 Jesper Krogh111 Zoltán Kutalik112,113 Maren Lang3 Glyn Lewis114 Yihan Li50 Donald J. MacIntyre115,116 Pamela AF Madden102 Jonathan Marchine117 Hamdi Mbarek118,64 Peter McGuffin77 Divya Mehta119 Andres Metspalu92,120 Christel M. Middeldorp64 Evelin Mihailov92,121 Lili Milani92 Grant W. Montgomery122 Sara Mostafavi123,124 Niamh Mullins77 Matthias Nauck125,126 Bernard Ng124 Merete Nordentoft67,127 Dale R. Nyholt128 Michael C. O’Donovan129 Paul F. O’Reilly77 Hogni Oskarsson130 Michael J. Owen129 Sara A. Paciga131 Carsten Bøcker Pedersen66,67,8 Marianne Giørtz Pedersen66,67,8 Nancy L. Pedersen132 Michele L. Pergadia133 Roseann E. Peterson11,71 Erik Pettersson134 Wouter J. Peyrot43 David J. Porteous135 Danielle Posthuma136,137 James B. Potash138 Jorge A. Quiroz139 John P. Rice102 Brien P. Riley71 Margarita Rivera77,140 Douglas M. Ruderfer141 Saira Saeed Mirza24 Robert Schoevers142 Ling Shen107 Jianxin Shi143 Engilbert Sigurdsson144 Grant CB Sinnamon145 Johannes H. Smit43 Daniel J. Smith146 Jordan W. Smoller86 Hreinn Stephansson147 Stacy Steinberg147 Jana Strohmaier3 Katherine E. Tansey148 Alexander Teumer149 Wesley Thompson100,135,150,151,152 Pippa A. Thomson135 Thorgeir E. Thorgeirsson147 Jens Treutlein3 Maciej Trzaskowski153 Daniel Umbricht154 Sandra van der Auwera155 Gerard van Grootheest43 Albert M. van Hemert156 Alexander Viktorin132 Henry Völzke149 Yunpeng Wang67,100,151 Bradley T. Webb157 Myrna M. Weissman158,159 Jürgen Wellmann74 Gonneke Willemsen64 Hualin S. Xi160 Bernhard T. Baune68 Douglas H. R. Blackwood65 Dorret I. Boomsma64 Anders D. Børglum61,62,67 Henriette N. Buttenschøn62,67,161 Sven Cichon12,162,163,164 Enrico Domenici165 Jonathan Flint50,166 Hans J. Grabe155 Steven P. Hamilton167 Kenneth S. Kendler71 Qingqin S. Li168 Susanne Lucae106 Patrik K. Magnusson132 Andrew M. McIntosh65,83 Ole Mors67,169 Preben Bo Mortensen62,8,67 Bertram Müller-Myhsok69,70,170 Brenda WJH Penninx43 Roy H. Perlis87,171 Martin Preisig76 Catherine Schaefer107 Jordan W. Smoller87,88 Kari Stephansson147 Henning Tiemeier24,56,57 Rudolf Uher172 Thomas Werge100,150,173 Ashley R. Winslow174,175 Gerome Breen77,176 Douglas F. Levinson177 Cathryn M. Lewis77,178 Naomi R. Wray5,153 Patrick F. Sullivan134,179,180 23MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. 24Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands. 25Psychiatry, Dokuz Eylul University School Of Medicine, Izmir, TR, Turkey. 26Centre for Population Health Sciences, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH8 9AG, UK. 27Internal Medicine, Erasmus MC, Rotterdam, NL, Netherlands. 28Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland. 29National Institute for Health and Welfare, Helsinki, Finland. 30Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 31Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland. 32Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. 33Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland. 34Folkhalsan Research Centre, Helsinki, Finland. 35Vasa Central Hospital, Vasa, Finland. 36Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland. 37Department of Children and Yond People and Families, National Institute for Health and elfare, Oulu, Finland. 38Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, Imperial College London, London, UK. 39Unit of Primary Care, Oulu University Hospital, Oulu, Finland. 40MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK. 41School of Social and Community Medicine, University of Bristol, Bristol, UK. 42Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA. 43Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, Netherlands. 44Geriatric Unit, ASF, Florence, Italy. 45University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, Netherlands. 46University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. 47Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Netherlands. 48University of Groningen, University Medical Center Groningen, Interdisciplinary Center for Psychiatric Epidemiology, Groningen, Netherlands. 49University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, Netherlands. 50Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 51Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 52Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 53School of Women’s and Infant’s Health, The University of Western Australia, Crawley, Australia. 54Department of Physiology, University of Toronto, Toronto, Ontario, Canada. 55Center for Bone and Arthritis Research, Institute of Medicin, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 56Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Netherlands. 57Psychiatry, Erasmus MC, Rotterdam, Netherlands. 58Medical and Population Genetics, Broad Institute, Cambridge, USA. 59Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, USA. 60Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany. 61Department of Biomedicine, Aarhus University, Aarhus, Denmark. 62iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark. 63iSPYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. 64Dept of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands. 65Division of Psychiatry, University of Edinburgh, Edinburgh, UK. 66Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. 67iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. 68Discipline of Psychiatry, University of Adelaide, Adelaide, Australia. 69Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. 70Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 71Department of Psychiatry, Virginia Commonwealth University, Richmond, USA. 72Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. 73Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, USA. 74Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, UK. 75Human Genetics, Wellcome Trust Sanger Institute, Cambridge, UK. 76Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland. 77MRC Social Genetic and Developmental Psychiatry Centre, King’s College London, London, UK. 78University of Oxford, Oxford, UK. 79Psychological Medicine, Cardiff University, Cardiff, UK. 80Department of Psychiatry, University of Marburg, Marburg, Germany. 81Department of Psychiatry, University of Münster, Münster, Germany. 82Avera Institute for Human Genetics, Sioux Falls, USA. 83Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. 84EMGO+ Institute, VU University Medical Center, Amsterdam, Netherlands. 85Neurology, Brigham and Women’s Hospital, Boston, USA. 86Stanley Center for Psychiatric Research, Broad Institute, Cambridge, USA. 87Department of Psychiatry, Massachusetts General Hospital, Boston, USA. 88Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, USA. 89Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK. 90Division of Endocrinology, Children’s Hospital Boston, Boston, USA. 91Department of Genetics, Harvard Medical School, Boston, USA. 92Estonian Genome Center, University of Tartu, Tartu, Estonia. 93Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA. 94Department of Mathematics, Massachusetts Institute of Technology, Cambridge, USA. 95Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 96Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 97Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark. 98Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. 99Danish Headache Centre, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark. 100Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region of Denmark, Roskilde, Denmark. 101iPSYCH, The Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, Denmark. 102Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, USA. 103Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany. 104Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 105Department of Medicine, Harvard Medical School, Boston, USA. 106Max Planck Institute of Psychiatry, Munich, Germany. 107Division of Research, Kaiser Permanente Northern California, Oakland, USA. 108Centre for Addiction and Mental Health, Toronto, Canada. 109Department of Psychiatry, University of Toronto, Toronto, Canada. 110Psychiatry & The Behavioral Sciences, University of Southern California, Los Angeles, USA. 111Department of Endocrinology at Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark. 112Swiss Institute of Bioinformatics, Lausanne, Switzerland. 113Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland. 114Division of Psychiatry, University College London, London, UK. 115Mental Health NHS 24, Glasgow, UK. 116Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 117Statistics, University of Oxford, Oxford, UK. 118EMGO+ Institute for Health and Care Research, Amsterdam, Netherlands. 119School of Psychology and Counseling, Queensland University of Technology, Brisbane, Australia. 120Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. 121Estonian Biocentre, Tartu, Estonia. 122Institute for Molecular Biology, University of Queensland, Brisbane, Australia. 123Medical Genetics, University of British Columbia, Vancouver, Canada. 124Statistics, University of British Columbia, Vancouver, Canada. 125DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, Matthias Nauck, Greifswald, Germany. 126Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. 127Mental Health Centre Copenhagen, Copenhagen Universtity Hospital, Copenhagen, Denmark. 128Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. 129MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. 130Humus, Reykjavik, Iceland. 131Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, USA. 132Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 133Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, USA. 134Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 135Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, UK. 136Complex Trait Genetics, VU University Amsterdam, Amsterdam, Netherlands. 137Clinical Genetics, VU University Medical Center, Amsterdam, Netherlands. 138Psychiatry, University of Iowa, Iowa City, USA. 139Solid GT, Boston, USA. 140Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain. 141Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA. 142Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. 143Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA. 144Faculty of Medicine, Department of Psychiatry, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 145School of Medicine and Dentistry, James Cook University, Townsville, Australia. 146Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. 147deCODE Genetics/Amgen, Reykjavik, Iceland. 148College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK. 149Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. 150iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. 151KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 152Department of Psychiatry, University of California, San Diego, San Diego, USA. 153Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. 154Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Medicine Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 155Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany. 156Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands. 157Virginia Institute of Psychiatric & Behavioral Genetics, Virginia Commonwealth University, Richmond, USA. 158Psychiatry, Columbia University College of Physicians and Surgeons, New York, USA. 159Division of Epidemiology, New York State Psychiatric Institute, New York, USA. 160Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, USA. 161Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark. 162Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. 163Department of Biomedicine, University of Basel, Basel, CH, Switzerland. 164Division of Medical Genetics, University of Basel, Basel, CH, Switzerland. 165Centre for Integrative Biology, Università degli Studi di Trento, Trento, Italy. 166Psychiatry, University of California Los Angeles, Los Angeles, USA. 167Psychiatry, Kaiser Permanente Northern California, San Francisco, USA. 168Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, USA. 169Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Denmark. 170Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 171Psychiatry, Harvard Medical School, Boston, USA. 172Psychiatry, Dalhousie University, Halifax, Canada. 173Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 174Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, USA. 175Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. 176NIHR BRC for Mental Health, King’s College London, London, UK. 177Psychiatry & Behavioral Sciences, Stanford University, Stanford, USA. 178Department of Medical & Molecular Genetics, King’s College London, London, UK. 179Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA. 180Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA.

Published
2017

15. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

Author

Zhou, Wei, Brumpton, Ben, Kabil, Omer, Gudmundsson, Julius, Thorleifsson, Gudmar, Weinstock, Josh, Zawistowski, Matthew, Nielsen, Jonas B., Chaker, Layal, Medici, Marco, Teumer, Alexander, Naitza, Silvia, Sanna, Serena, Schultheiss, Ulla T., Cappola, Anne, Karjalainen, Juha, Kurki, Mitja, Oneka, Morgan, Taylor, Peter, and Fritsche, Lars G.

Subjects
THYROID cancer, THYROTROPIN, THYROID gland tumors, BENIGN tumors, GENETIC markers, THYROID gland, THYROTROPIN receptors
Abstract

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors. Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. Here, the authors conduct a GWAS and suggest protective effect of higher TSH on risk of thyroid cancer and goitre. [ABSTRACT FROM AUTHOR]

Published
2020
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16. Validated inference of smoking habits from blood with a finite DNA methylation marker set.

Author

Maas, Silvana C. E., Vidaki, Athina, Wilson, Rory, Teumer, Alexander, Liu, Fan, van Meurs, Joyce B. J., Uitterlinden, André G., Boomsma, Dorret I., de Geus, Eco J. C., Willemsen, Gonneke, van Dongen, Jenny, van der Kallen, Carla J. H., Slagboom, P. Eline, Beekman, Marian, van Heemst, Diana, van den Berg, Leonard H., Duijts, Liesbeth, Jaddoe, Vincent W. V., Ladwig, Karl-Heinz, and Kunze, Sonja

Subjects
DNA methylation, GENETIC markers, DNA, PASSIVE smoking, SMOKING cessation, HISTONE methylation
Abstract

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications. [ABSTRACT FROM AUTHOR]

Published
2019
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17. 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

Author

Gorski, Mathias, van der Most, Peter J., Teumer, Alexander, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Nolte, Ilja M., Cocca, Massimiliano, Taliun, Daniel, Gomez, Felicia, Li, Yong, Tayo, Bamidele, Tin, Adrienne, Feitosa, Mary F., Aspelund, Thor, Attia, John, Biffar, Reiner, Bochud, Murielle, Boerwinkle, Eric, and Borecki, Ingrid

Abstract

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples. [ABSTRACT FROM AUTHOR]

Published
2017
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19. Two statistical criteria to choose the method for dilution correction in metabolomic urine measurements.

Author

Hertel, Johannes, Auwera, Sandra, Friedrich, Nele, Wittfeld, Katharina, Pietzner, Maik, Budde, Kathrin, Teumer, Alexander, Kocher, Thomas, Nauck, Matthias, and Grabe, Hans

Subjects
METABOLOMICS, URINALYSIS, CREATININE, DATA integration, ANALYSIS of variance
Abstract

Introduction: Different normalization methods are available for urinary data. However, it is unclear which method performs best in minimizing error variance on a certain data-set as no generally applicable empirical criteria have been established so far. Objectives: The main aim of this study was to develop an applicable and formally correct algorithm to decide on the normalization method without using phenotypic information. Methods: We proved mathematically for two classical measurement error models that the optimal normalization method generates the highest correlation between the normalized urinary metabolite concentrations and its blood concentrations or, respectively, its raw urinary concentrations. We then applied the two criteria to the urinary H-NMR measured metabolomic data from the Study of Health in Pomerania (SHIP-0; n = 4068) under different normalization approaches and compared the results with in silico experiments to explore the effects of inflated error variance in the dilution estimation. Results: In SHIP-0, we demonstrated consistently that probabilistic quotient normalization based on aligned spectra outperforms all other tested normalization methods. Creatinine normalization performed worst, while for unaligned data integral normalization seemed to most reasonable. The simulated and the actual data were in line with the theoretical modeling, underlining the general validity of the proposed criteria. Conclusions: The problem of choosing the best normalization procedure for a certain data-set can be solved empirically. Thus, we recommend applying different normalization procedures to the data and comparing their performances via the statistical methodology explicated in this work. On the basis of classical measurement error models, the proposed algorithm will find the optimal normalization method. [ABSTRACT FROM AUTHOR]

Published
2017
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20. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Author

Pattaro, Cristian, Teumer, Alexander, Gorski, Mathias, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Yong Li, Taliun, Daniel, Olden, Matthias, Foster, Meredith, Qiong Yang, Ming-Huei Chen, Pers, Tune H., Johnson, Andrew D., Yi-An Ko, Fuchsberger, Christian, and Tayo, Bamidele

Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. [ABSTRACT FROM AUTHOR]

Published
2016
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21. Author Correction: GWAS of thyroid stimulating hormone highlights the pleiotropic effects and inverse association with thyroid cancer.

Author

Zhou, Wei, Brumpton, Ben, Kabil, Omer, Gudmundsson, Julius, Thorleifsson, Gudmar, Weinstock, Josh, Zawistowski, Matthew, Nielsen, Jonas B., Chaker, Layal, Medici, Marco, Teumer, Alexander, Naitza, Silvia, Sanna, Serena, Schultheiss, Ulla T., Cappola, Anne, Karjalainen, Juha, Kurki, Mitja, Oneka, Morgan, Taylor, Peter, and Fritsche, Lars G.

Subjects
THYROTROPIN, THYROID cancer, GENOME-wide association studies, MISSENSE mutation
Abstract

At the other association signal, missense variant I TG i p.P118L (rs114322847, MAF = 2.4%, effect size = -0.17 SD, 95% CI = -0.20 to -0.14 SD, I P i -value = 1.87 × 10 SP -26 sp ) is in strong LD ( I r i SP 2 sp = 0.92) with the most strongly associated variant rs118039499 (intronic) (Supplementary Table 2, Supplementary Figure 4)'. The original version incorrectly read 'In the HUNT study, the missense variant I TG i p.G67S (rs116340633, MAF = 1.8%, effect size = 0.77 SD, 95% CI = 0.73-0.82 SD, I P i -value = 1.07 × 10 SP -21 sp ) is in strong LD ( I r i SP 2 sp = 0.99) with the most strongly associated variant rs117074997 (intronic). [Extracted from the article]

Published
2021
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22. Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits.

Author

Auer, Paul L, Teumer, Alexander, Schick, Ursula, O'Shaughnessy, Andrew, Lo, Ken Sin, Chami, Nathalie, Carlson, Chris, de Denus, Simon, Dubé, Marie-Pierre, Haessler, Jeff, Jackson, Rebecca D, Kooperberg, Charles, Perreault, Louis-Philippe Lemieux, Nauck, Matthias, Peters, Ulrike, Rioux, John D, Schmidt, Frank, Turcot, Valérie, Völker, Uwe, and Völzke, Henry

Subjects
*HEMATOLOGY, *INTERNAL medicine, *NEUTROPENIA, *GENETIC mutation, *HEREDITY
Abstract

Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10−13). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10−22) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10−7) and WBC count (P = 3.1 × 10−5). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits. [ABSTRACT FROM AUTHOR]

Published
2014
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23. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.

Author

Köttgen, Anna, Albrecht, Eva, Teumer, Alexander, Vitart, Veronique, Krumsiek, Jan, Hundertmark, Claudia, Pistis, Giorgio, Ruggiero, Daniela, O'Seaghdha, Conall M, Haller, Toomas, Yang, Qiong, Tanaka, Toshiko, Johnson, Andrew D, Kutalik, Zoltán, Smith, Albert V, Shi, Julia, Struchalin, Maksim, Middelberg, Rita P S, Brown, Morris J, and Gaffo, Angelo L

Subjects
GENOMES, BLOOD serum analysis, GOUT treatment, URATES, GOUT, GENE expression, PREVENTION
Abstract

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. [ABSTRACT FROM AUTHOR]

Published
2013
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24. New gene functions in megakaryopoiesis and platelet formation.

Author

Gieger, Christian, Radhakrishnan, Aparna, Cvejic, Ana, Tang, Weihong, Porcu, Eleonora, Pistis, Giorgio, Serbanovic-Canic, Jovana, Elling, Ulrich, Goodall, Alison H., Labrune, Yann, Lopez, Lorna M., Mägi, Reedik, Meacham, Stuart, Okada, Yukinori, Pirastu, Nicola, Sorice, Rossella, Teumer, Alexander, Voss, Katrin, Zhang, Weihua, and Ramirez-Solis, Ramiro

Subjects
BLOOD platelets, HEMOSTASIS, GENOMICS, GENE expression, GENE silencing, META-analysis, ZEBRA danio, DROSOPHILA melanogaster
Abstract

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function. [ABSTRACT FROM AUTHOR]

Published
2011
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25. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Author

Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Hua Zhao, Jing, and Aulchenko, Yurii

Subjects
REGULATION of blood pressure, BLOOD circulation disorders, CARDIOVASCULAR diseases risk factors, HUMAN genetics, RESTRICTED environmental stimulation, GENETIC code
Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (?140?mm?Hg systolic blood pressure or??90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

Published
2011
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26. Moderation of Adult Depression by a Polymorphism in the FKBP5 Gene and Childhood Physical Abuse in the General Population.

Author

Appel, Katja, Schwahn, Christian, Mahler, Jessie, Schulz, Andrea, Spitzer, Carsten, Fenske, Kristin, Stender, Jan, Barnow, Sven, John, Ulrich, Teumer, Alexander, Biffar, Reiner, Nauck, Matthias, Völzke, Henry, Freyberger, Harald J., and Grabe, Hans J.

Subjects
DEPRESSION in adolescence, GENETIC polymorphisms, CHILD abuse, PHYSICAL abuse, HYPOTHALAMIC-pituitary-adrenal axis, MOLECULAR chaperones, GLUCOCORTICOID receptors
Abstract

Childhood maltreatment and depressive disorders have both been associated with a dysregulation of the hypothalamic-pituitary-adrenal axis. The FKBP5 gene codes for a co-chaperone regulating the glucocorticoid-receptor sensitivity. Previous evidence suggests that subjects carrying the TT genotype of the FKBP5 gene single-nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to adverse effects of experimental stress. We therefore tested the hypothesis of an interaction of childhood abuse with rs1360780 in predicting adult depression. In all, 2157 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and Childhood Trauma Questionnaire. The DSM-IV diagnosis of major depressive disorder (MDD) was assessed by interview. Genotypes of rs1360780 were taken from the Affymetrix Human SNP Array 6.0. Significant interaction (p=0.006) of physical abuse with the TT genotype of rs1360780 was found increasing the BDI-II score to 17.4 (95% confidence interval (CI)=12.0-22.9) compared with 10.0 (8.2-11.7) in exposed CC/CT carriers. Likewise, the adjusted odds ratio for MDD in exposed TT carriers was 8.2 (95% CI=1.9-35.0) compared with 1.3 (0.8-2.3) in exposed subjects with CC/CT genotypes. Relative excess risk due to interaction (RERI) analyses confirmed a significant additive interaction effect (RERI=6.8; 95% CI=0.64-33.7; p<0.05). In explorative analyses, the most severe degree of sexual and emotional abuse also yielded significant interaction effects (p<0.05). This study revealed interactions between physical abuse and rs1360780 of the FKBP5 gene, confirming its role in the individual susceptibility to depression. Given the large effect sizes, rs1360780 could be included into prediction models for depression in individuals exposed to childhood abuse. [ABSTRACT FROM AUTHOR]

Published
2011
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27. A genome-wide association study of metabolic traits in human urine.

Author

Suhre, Karsten, Wallaschofski, Henri, Raffler, Johannes, Friedrich, Nele, Haring, Robin, Michael, Kathrin, Wasner, Christina, Krebs, Alexander, Kronenberg, Florian, Chang, David, Meisinger, Christa, Wichmann, H-Erich, Hoffmann, Wolfgang, Völzke, Henry, Völker, Uwe, Teumer, Alexander, Biffar, Reiner, Kocher, Thomas, Felix, Stephan B., and Illig, Thomas

Subjects
DETOXIFICATION (Alternative medicine), URINALYSIS, KIDNEY diseases, DRUG toxicity, PATHOLOGICAL physiology, NUCLEAR magnetic resonance spectroscopy
Abstract

We present a genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body. Using NMR spectroscopy, we tested for associations between 59 metabolites in urine from 862 male participants in the population-based SHIP study. We replicated the results using 1,039 additional samples of the same study, including a 5-year follow-up, and 992 samples from the independent KORA study. We report five loci with joint P values of association from 3.2 × 10−19 to 2.1 × 10−182. Variants at three of these loci have previously been linked with important clinical outcomes: SLC7A9 is a risk locus for chronic kidney disease, NAT2 for coronary artery disease and genotype-dependent response to drug toxicity, and SLC6A20 for iminoglycinuria. Moreover, we identify rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria. [ABSTRACT FROM AUTHOR]

Published
2011
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28. New loci associated with kidney function and chronic kidney disease.

Author

Köttgen, Anna, Pattaro, Cristian, Böger, Carsten A., Fuchsberger, Christian, Olden, Matthias, Glazer, Nicole L., Parsa, Afshin, Xiaoyi Gao, Qiong Yang, Smith, Albert V., O'Connell, Jeffrey R., Man Li, Schmidt, Helena, Tanaka, Toshiko, Isaacs, Aaron, Ketkar, Shamika, Shih-Jen Hwang, Johnson, Andrew D., Dehghan, Abbas, and Teumer, Alexander

Subjects
LOCUS (Genetics), KIDNEY diseases, FOCAL segmental glomerulosclerosis, NEOVASCULARIZATION, BLOOD-vessel development, META-analysis, GENE therapy, GENETICS
Abstract

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney. [ABSTRACT FROM AUTHOR]

Published
2010
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29. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.

Author

Soranzo, Nicole, Spector, Tim D., Mangino, Massimo, Kühnel, Brigitte, Rendon, Augusto, Teumer, Alexander, Willenborg, Christina, Wright, Benjamin, Li Chen, Mingyao Li, Salo, Perttu, Voight, Benjamin F., Burns, Philippa, Laskowski, Roman A., Yali Xue, Menzel, Stephan, Altshuler, David, Bradley, John R., Bumpstead, Suzannah, and Burnett, Mary-Susan

Subjects
GENOMES, HEMATOLOGY, ERYTHROCYTES, BLOOD cell count, MYOCARDIAL infarction, MALABSORPTION syndromes
Abstract

The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations. [ABSTRACT FROM AUTHOR]

Published
2009
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30. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.

Author

Ganesh, Santhi K., Zakai, Neil A., van Rooij, Frank J. A., Soranzo, Nicole, Smith, Albert V., Nalls, Michael A., Ming-Huei Chen, Kottgen, Anna, Glazer, Nicole L., Dehghan, Abbas, Kuhnel, Brigitte, Aspelund, Thor, Qiong Yang, Tanaka, Toshiko, Jaffe, Andrew, Bis, Joshua C. M., Verwoert, Germaine C., Teumer, Alexander, Fox, Caroline S., and Guralnik, Jack M.

Subjects
ERYTHROCYTES, PHENOTYPES, BLOOD proteins, BLOOD cells, HEMOGLOBINS
Abstract

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 × 10−8 to 7 × 10−86). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures. [ABSTRACT FROM AUTHOR]

Published
2009
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31. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Author

Hofer, Edith, Roshchupkin, Gennady V., Adams, Hieab H. H., Knol, Maria J., Lin, Honghuang, Li, Shuo, Zare, Habil, Ahmad, Shahzad, Armstrong, Nicola J., Satizabal, Claudia L., Bernard, Manon, Bis, Joshua C., Gillespie, Nathan A., Luciano, Michelle, Mishra, Aniket, Scholz, Markus, Teumer, Alexander, Xia, Rui, Jian, Xueqiu, and Mosley, Thomas H.

Subjects
GENETIC correlations, MENTAL illness, NEUROLOGICAL disorders, CARDIAC research, ADULTS, WNT genes
Abstract

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging. Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults. [ABSTRACT FROM AUTHOR]

Published
2020
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32. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Author

Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P., Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B., Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y., Bansal, Nisha, Feitosa, Mary F., Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, and Hoppmann, Anselm

Subjects
ALBUMINURIA, DISEASE progression, GENE expression, PROTEINURIA, ENDOCYTOSIS
Abstract

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. Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies. [ABSTRACT FROM AUTHOR]

Published
2019
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33. Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.

Author

Shungin, Dmitry, Haworth, Simon, Divaris, Kimon, Agler, Cary S., Kamatani, Yoichiro, Keun Lee, Myoung, Grinde, Kelsey, Hindy, George, Alaraudanjoki, Viivi, Pesonen, Paula, Teumer, Alexander, Holtfreter, Birte, Sakaue, Saori, Hirata, Jun, Yu, Yau-Hua, Ridker, Paul M., Giulianini, Franco, Chasman, Daniel I., Magnusson, Patrik K. E., and Sudo, Takeaki

Abstract

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health. Dental caries and periodontitis are among the most common medical conditions. Here, the authors report a GWAS for measures of oral health that reveals 47 risk loci for caries, find genetic correlation with 31 other complex traits and use Mendelian randomization analyses to explore potential causal relationships. [ABSTRACT FROM AUTHOR]

Published
2019
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34. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Author

Teumer, Alexander, Chaker, Layal, Groeneweg, Stefan, Li, Yong, Di Munno, Celia, Barbieri, Caterina, Schultheiss, Ulla T., Traglia, Michela, Ahluwalia, Tarunveer S., Akiyama, Masato, Appel, Emil Vincent R., Arking, Dan E., Arnold, Alice, Astrup, Arne, Beekman, Marian, Beilby, John P., Bekaert, Sofie, Boerwinkle, Eric, Brown, Suzanne J., and De Buyzere, Marc

Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets. Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme. [ABSTRACT FROM AUTHOR]

Published
2018
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35. Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.

Author

Vojinovic, Dina, Adams, Hieab H., Jian, Xueqiu, Yang, Qiong, Smith, Albert Vernon, Bis, Joshua C., Teumer, Alexander, Scholz, Markus, Armstrong, Nicola J., Hofer, Edith, Saba, Yasaman, Luciano, Michelle, Bernard, Manon, Trompet, Stella, Yang, Jingyun, Gillespie, Nathan A., van der Lee, Sven J., Neumann, Alexander, Ahmad, Shahzad, and Andreassen, Ole A.

Abstract

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = −0.59, p-value = 3.14 × 10−6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology. An increase in the volume of the brain lateral ventricles is a sign of normal aging, but can also be associated with neurological and psychiatric disorders. Here, Vojinovic et al. identify seven genetic loci in a GWA study for ventricular volume in 23,500 individuals and find correlation with thalamus volume. [ABSTRACT FROM AUTHOR]

Published
2018
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36. Genome-wide association meta-analysis of coronary artery disease and periodontitis reveals a novel shared risk locus.

Author

Munz, Matthias, Richter, Gesa M., Loos, Bruno G., Jepsen, Søren, Divaris, Kimon, Offenbacher, Steven, Teumer, Alexander, Holtfreter, Birte, Kocher, Thomas, Bruckmann, Corinna, Jockel-Schneider, Yvonne, Graetz, Christian, Munoz, Loreto, Bhandari, Anita, Tennstedt, Stephanie, Staufenbiel, Ingmar, van der Velde, Nathalie, Uitterlinden, André G., de Groot, Lisette C. P. G. M., and Wellmann, Jürgen

Abstract

Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (PAgP-Ger < 0.05; PCAD < 5 × 10−8; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02-1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05-1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense. [ABSTRACT FROM AUTHOR]

Published
2018
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37. Is there a male-specific effect on hypertension?

Author

Dankowski, Theresa, Schillert, Arne, Teumer, Alexander, Blankenberg, Stefan, Dörr, Marcus, Franke, Andre, Lieb, Wolfgang, König, Inke, and Ziegler, Andreas

Subjects
HYPERTENSION, METABOLIC disorders
Abstract

A letter to the editor in response to an article " Male-specific genetic effect on hypertension and metabolic disorders" published in the year 2014 of the issue by S.G. Heo et al is presented.

Published
2015
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38. Corrigendum: 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

Author

Gorski, Mathias, Most, Peter J. van der, Teumer, Alexander, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Nolte, Ilja M., Cocca, Massimiliano, Taliun, Daniel, Gomez, Felicia, Li, Yong, Tayo, Bamidele, Tin, Adrienne, Feitosa, Mary F., Aspelund, Thor, Attia, John, Biffar, Reiner, Bochud, Murielle, Boerwinkle, Eric, and Borecki, Ingrid

Abstract

This corrects the article DOI: 10.1038/srep45040 [ABSTRACT FROM AUTHOR]

Published
2017
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39. Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation.

Author

Artigas, María Soler, Wain, Louise V., Miller, Suzanne, Kheirallah, Abdul Kader, Huffman, Jennifer E., Ntalla, Ioanna, Shrine, Nick, Obeidat, Ma'en, Trochet, Holly, McArdle, Wendy L., Alves, Alexessander Couto, Hui, Jennie, Zhao, Jing Hua, Joshi, Peter K., Teumer, Alexander, Albrecht, Eva, Imboden, Medea, Rawal, Rajesh, Lopez, Lorna M., and Marten, Jonathan

Published
2015
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41. Rare coding variants and X-linked loci associated with age at menarche.

Author

Lunetta, Kathryn L., Day, Felix R., Sulem, Patrick, Ruth, Katherine S., Tung, Joyce Y., Hinds, David A., Esko, Tõnu, Elks, Cathy E., Altmaier, Elisabeth, He, Chunyan, Huffman, Jennifer E., Mihailov, Evelin, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Stolk, Lisette, Teumer, Alexander, Thompson, Deborah J., and Traglia, Michela

Published
2015
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42. 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. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. 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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