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2. Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Author

Keaton, Jacob, Kamali, Zoha, Xie, Tian, Vaez, Ahmad, Williams, Ariel, Goleva, Slavina, Ani, Alireza, Evangelou, Evangelos, Hellwege, Jacklyn, Yengo, Loic, Young, William, Traylor, Matthew, Giri, Ayush, Zheng, Zhili, Zeng, Jian, Chasman, Daniel, Morris, Andrew, Caulfield, Mark, Hwang, Shih-Jen, Kooner, Jaspal, Conen, David, Attia, John, Morrison, Alanna, Loos, Ruth, Kristiansson, Kati, Schmidt, Reinhold, Hicks, Andrew, Pramstaller, Peter, Nelson, Christopher, Samani, Nilesh, Risch, Lorenz, Gyllensten, Ulf, Melander, Olle, Riese, Harriette, Wilson, James, Campbell, Harry, Rich, Stephen, Psaty, Bruce, Lu, Yingchang, Guo, Xiuqing, Rice, Kenneth, Vollenweider, Peter, Sundström, Johan, Langenberg, Claudia, Tobin, Martin, Giedraitis, Vilmantas, Luan, Jianan, Tuomilehto, Jaakko, Kutalik, Zoltan, Ripatti, Samuli, Salomaa, Veikko, Girotto, Giorgia, Trompet, Stella, Jukema, J, van der Harst, Pim, Ridker, Paul, Giulianini, Franco, Vitart, Veronique, Goel, Anuj, Watkins, Hugh, Harris, Sarah, Deary, Ian, van der Most, Peter, Oldehinkel, Albertine, Keavney, Bernard, Hayward, Caroline, Campbell, Archie, Boehnke, Michael, Scott, Laura, Boutin, Thibaud, Mamasoula, Chrysovalanto, Järvelin, Marjo-Riitta, Peters, Annette, Gieger, Christian, Lakatta, Edward, Cucca, Francesco, Hui, Jennie, Knekt, Paul, Enroth, Stefan, De Borst, Martin, Polašek, Ozren, Concas, Maria, Catamo, Eulalia, Cocca, Massimiliano, Li-Gao, Ruifang, Hofer, Edith, Schmidt, Helena, Spedicati, Beatrice, Waldenberger, Melanie, Strachan, David, Laan, Maris, Teumer, Alexander, Dörr, Marcus, Gudnason, Vilmundur, Cook, James, Ruggiero, Daniela, Kolcic, Ivana, Boerwinkle, Eric, Traglia, Michela, and Lehtimäki, Terho

Subjects
Female, Humans, Male, Blood Pressure, Genetic Predisposition to Disease, Genetic Risk Score, Genome-Wide Association Study, Hypertension, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Risk Factors
Abstract

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P

Published
2024

3. Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

Author

Boen, Rune, Kaufmann, Tobias, van der Meer, Dennis, Frei, Oleksandr, Agartz, Ingrid, Ames, David, Andersson, Micael, Armstrong, Nicola, Artiges, Eric, Atkins, Joshua, Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret, Brodaty, Henry, Brosch, Katharina, Buckner, Randy, Cairns, Murray, Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden, Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike, de Geus, Eco, de Zubicaray, Greig, Desrivières, Sylvane, Doherty, Joanne, Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon, Forstner, Andreas, Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David, Goltermann, Janik, Grabe, Hans, Green, Melissa, Groenewold, Nynke, Grotegerd, Dominik, Grøntvedt, Gøril, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne, Henskens, Frans, Holmes, Avram, Håberg, Asta, Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik, Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David, Liu, Jingyu, Loughnan, Robert, Mather, Karen, McMahon, Katie, McRae, Allan, Medland, Sarah, Meinert, Susanne, Moreau, Clara, Morris, Derek, Mowry, Bryan, Mühleisen, Thomas, Nenadić, Igor, Nöthen, Markus, Nyberg, Lars, Ophoff, Roel, Owen, Michael, Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago, Sachdev, Perminder, Sando, Sigrid, Schall, Ulrich, Scott, Rodney, Selbæk, Geir, Shumskaya, Elena, Silva, Ana, Sisodiya, Sanjay, Stein, Frederike, Stein, Dan, Straube, Benjamin, Streit, Fabian, Strike, Lachlan, Teumer, Alexander, and Teutenberg, Lea

Subjects
15q11.2 BP1-BP2, 1q21.1 distal, Brain structure, Copy number variants, Intraindividual variability, Magnetic resonance imaging, Humans, Chromosome Deletion, Brain, Magnetic Resonance Imaging, Abnormalities, Multiple, Chromosomes, Human, Pair 15, DNA Copy Number Variations
Abstract

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individuals regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Published
2024

4. Association analysis between an epigenetic alcohol risk score and blood pressure

Author

Bui, Helena, Keshawarz, Amena, Wang, Mengyao, Lee, Mikyeong, Ratliff, Scott M, Lin, Lisha, Birditt, Kira S, Faul, Jessica D, Peters, Annette, Gieger, Christian, Delerue, Thomas, Kardia, Sharon LR, Zhao, Wei, Guo, Xiuqing, Yao, Jie, Rotter, Jerome I, Li, Yi, Liu, Xue, Liu, Dan, Tavares, Juliana F, Pehlivan, Gökhan, Breteler, Monique MB, Karabegovic, Irma, Ochoa-Rosales, Carolina, Voortman, Trudy, Ghanbari, Mohsen, van Meurs, Joyce BJ, Nasr, Mohamed Kamal, Dörr, Marcus, Grabe, Hans J, London, Stephanie J, Teumer, Alexander, Waldenberger, Melanie, Weir, David R, Smith, Jennifer A, Levy, Daniel, Ma, Jiantao, and Liu, Chunyu

Subjects
Biological Sciences, Genetics, Alcoholism, Alcohol Use and Health, Prevention, Human Genome, Cardiovascular, Hypertension, Clinical Research, Substance Misuse, Good Health and Well Being, Humans, Epigenesis, Genetic, Alcohol Drinking, Blood Pressure, Female, Male, DNA Methylation, Middle Aged, Cross-Sectional Studies, Genome-Wide Association Study, Risk Factors, CpG Islands, Aged, Adult, Epigenetic risk score, DNA methylation, Blood pressure, Alcohol, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

BackgroundEpigenome-wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits.ResultsWe implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p

Published
2024

5. Association analysis between an epigenetic alcohol risk score and blood pressure

Author

Helena Bui, Amena Keshawarz, Mengyao Wang, Mikyeong Lee, Scott M. Ratliff, Lisha Lin, Kira S. Birditt, Jessica D. Faul, Annette Peters, Christian Gieger, Thomas Delerue, Sharon L. R. Kardia, Wei Zhao, Xiuqing Guo, Jie Yao, Jerome I. Rotter, Yi Li, Xue Liu, Dan Liu, Juliana F. Tavares, Gökhan Pehlivan, Monique M. B. Breteler, Irma Karabegovic, Carolina Ochoa-Rosales, Trudy Voortman, Mohsen Ghanbari, Joyce B. J. van Meurs, Mohamed Kamal Nasr, Marcus Dörr, Hans J. Grabe, Stephanie J. London, Alexander Teumer, Melanie Waldenberger, David R. Weir, Jennifer A. Smith, Daniel Levy, Jiantao Ma, and Chunyu Liu

Subjects
Epigenetic risk score, DNA methylation, Blood pressure, Hypertension, Alcohol, Medicine, Genetics, QH426-470
Abstract

Abstract Background Epigenome‐wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits. Results We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p

Published
2024
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6. Distinct genetic liability profiles define clinically relevant patient strata across common diseases

Author

Trastulla, Lucia, Dolgalev, Georgii, Moser, Sylvain, Jiménez-Barrón, Laura T., Andlauer, Till F. M., von Scheidt, Moritz, Budde, Monika, Heilbronner, Urs, Papiol, Sergi, Teumer, Alexander, Homuth, Georg, Völzke, Henry, Dörr, Marcus, Falkai, Peter, Schulze, Thomas G., Gagneur, Julien, Iorio, Francesco, Müller-Myhsok, Bertram, Schunkert, Heribert, and Ziller, Michael J.

Published
2024
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8. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author

Sterenborg, Rosalie B. T. M., Steinbrenner, Inga, Li, Yong, Bujnis, Melissa N., Naito, Tatsuhiko, Marouli, Eirini, Galesloot, Tessel E., Babajide, Oladapo, Andreasen, Laura, Astrup, Arne, Åsvold, Bjørn Olav, Bandinelli, Stefania, Beekman, Marian, Beilby, John P., Bork-Jensen, Jette, Boutin, Thibaud, Brody, Jennifer A., Brown, Suzanne J., Brumpton, Ben, Campbell, Purdey J., Cappola, Anne R., Ceresini, Graziano, Chaker, Layal, Chasman, Daniel I., Concas, Maria Pina, Coutinho de Almeida, Rodrigo, Cross, Simone M., Cucca, Francesco, Deary, Ian J., Kjaergaard, Alisa Devedzic, Echouffo Tcheugui, Justin B., Ellervik, Christina, Eriksson, Johan G., Ferrucci, Luigi, Freudenberg, Jan, Fuchsberger, Christian, Gieger, Christian, Giulianini, Franco, Gögele, Martin, Graham, Sarah E., Grarup, Niels, Gunjača, Ivana, Hansen, Torben, Harding, Barbara N., Harris, Sarah E., Haunsø, Stig, Hayward, Caroline, Hui, Jennie, Ittermann, Till, Jukema, J. Wouter, Kajantie, Eero, Kanters, Jørgen K., Kårhus, Line L., Kiemeney, Lambertus A. L. M., Kloppenburg, Margreet, Kühnel, Brigitte, Lahti, Jari, Langenberg, Claudia, Lapauw, Bruno, Leese, Graham, Li, Shuo, Liewald, David C. M., Linneberg, Allan, Lominchar, Jesus V. T., Luan, Jian’an, Martin, Nicholas G., Matana, Antonela, Meima, Marcel E., Meitinger, Thomas, Meulenbelt, Ingrid, Mitchell, Braxton D., Møllehave, Line T., Mora, Samia, Naitza, Silvia, Nauck, Matthias, Netea-Maier, Romana T., Noordam, Raymond, Nursyifa, Casia, Okada, Yukinori, Onano, Stefano, Papadopoulou, Areti, Palmer, Colin N. A., Pattaro, Cristian, Pedersen, Oluf, Peters, Annette, Pietzner, Maik, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Punda, Ante, Ray, Debashree, Redmond, Paul, Richards, J. Brent, Ridker, Paul M., Russ, Tom C., Ryan, Kathleen A., Olesen, Morten Salling, Schultheiss, Ulla T., Selvin, Elizabeth, Siddiqui, Moneeza K., Sidore, Carlo, Slagboom, P. Eline, Sørensen, Thorkild I. A., Soto-Pedre, Enrique, Spector, Tim D., Spedicati, Beatrice, Srinivasan, Sundararajan, Starr, John M., Stott, David J., Tanaka, Toshiko, Torlak, Vesela, Trompet, Stella, Tuhkanen, Johanna, Uitterlinden, André G., van den Akker, Erik B., van den Eynde, Tibbert, van der Klauw, Melanie M., van Heemst, Diana, Verroken, Charlotte, Visser, W. Edward, Vojinovic, Dina, Völzke, Henry, Waldenberger, Melanie, Walsh, John P., Wareham, Nicholas J., Weiss, Stefan, Willer, Cristen J., Wilson, Scott G., Wolffenbuttel, Bruce H. R., Wouters, Hanneke J. C. M., Wright, Margaret J., Yang, Qiong, Zemunik, Tatijana, Zhou, Wei, Zhu, Gu, Zöllner, Sebastian, Smit, Johannes W. A., Peeters, Robin P., Köttgen, Anna, Teumer, Alexander, and Medici, Marco

Published
2024
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9. Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

Author

Mei, Hao, Simino, Jeannette, Li, Lianna, Jiang, Fan, Bis, Joshua C., Davies, Gail, Hill, W David, Xia, Charley, Gudnason, Vilmundur, Yang, Qiong, Lahti, Jari, Smith, Jennifer A., Kirin, Mirna, De Jager, Philip, Armstrong, Nicola J., Ghanbari, Mohsen, Kolcic, Ivana, Moran, Christopher, Teumer, Alexander, Sargurupremraj, Murali, Mahmud, Shamsed, Fornage, Myriam, Zhao, Wei, Satizabal, Claudia L., Polasek, Ozren, Räikkönen, Katri, Liewald, David C., Homuth, Georg, Callisaya, Michele, Mather, Karen A., Windham, B. Gwen, Zemunik, Tatijana, Palotie, Aarno, Pattie, Alison, van der Auwera, Sandra, Thalamuthu, Anbupalam, Knopman, David S., Rudan, Igor, Starr, John M., Wittfeld, Katharina, Kochan, Nicole A., Griswold, Michael E., Vitart, Veronique, Brodaty, Henry, Gottesman, Rebecca, Cox, Simon R., Psaty, Bruce M., Boerwinkle, Eric, Chasman, Daniel I., Grodstein, Francine, Sachdev, Perminder S., Srikanth, Velandai, Hayward, Caroline, Wilson, James F., Eriksson, Johan G., Kardia, Sharon L. R., Grabe, Hans J., Bennett, David A., Ikram, M. Arfan, Deary, Ian J., van Duijn, Cornelia M., Launer, Lenore, Fitzpatrick, Annette L., Seshadri, Sudha, Bressler, Jan, Debette, Stephanie, and Mosley, Jr, Thomas H.

Published
2024
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10. X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Author

Scholz, Markus, Horn, Katrin, Pott, Janne, Wuttke, Matthias, Kühnapfel, Andreas, Nasr, M. Kamal, Kirsten, Holger, Li, Yong, Hoppmann, Anselm, Gorski, Mathias, Ghasemi, Sahar, Li, Man, Tin, Adrienne, Chai, Jin-Fang, Cocca, Massimiliano, Wang, Judy, Nutile, Teresa, Akiyama, Masato, Åsvold, Bjørn Olav, Bansal, Nisha, Biggs, Mary L., Boutin, Thibaud, Brenner, Hermann, Brumpton, Ben, Burkhardt, Ralph, Cai, Jianwen, Campbell, Archie, Campbell, Harry, Chalmers, John, Chasman, Daniel I., Chee, Miao Ling, Chee, Miao Li, Chen, Xu, Cheng, Ching-Yu, Cifkova, Renata, Daviglus, Martha, Delgado, Graciela, Dittrich, Katalin, Edwards, Todd L., Endlich, Karlhans, Michael Gaziano, J., Giri, Ayush, Giulianini, Franco, Gordon, Scott D., Gudbjartsson, Daniel F., Hallan, Stein, Hamet, Pavel, Hartman, Catharina A., Hayward, Caroline, Heid, Iris M., Hellwege, Jacklyn N., Holleczek, Bernd, Holm, Hilma, Hutri-Kähönen, Nina, Hveem, Kristian, Isermann, Berend, Jonas, Jost B., Joshi, Peter K., Kamatani, Yoichiro, Kanai, Masahiro, Kastarinen, Mika, Khor, Chiea Chuen, Kiess, Wieland, Kleber, Marcus E., Körner, Antje, Kovacs, Peter, Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard K., Kuokkanen, Mikko, Kähönen, Mika, Lange, Leslie A., Lash, James P., Lehtimäki, Terho, Li, Hengtong, Lin, Bridget M., Liu, Jianjun, Loeffler, Markus, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K. E., Martin, Nicholas G., Matsuda, Koichi, Milaneschi, Yuri, Mishra, Pashupati P., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Mychaleckyj, Josyf C., März, Winfried, Nauck, Matthias, Nikus, Kjell, Nolte, Ilja M., Noordam, Raymond, Okada, Yukinori, Olafsson, Isleifur, Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Perola, Markus, Pirastu, Nicola, Polasek, Ozren, Porteous, David J., Poulain, Tanja, Psaty, Bruce M., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Rasheed, Humaira, Reilly, Dermot F., Rice, Kenneth M., Richmond, Anne, Ridker, Paul M., Rotter, Jerome I., Rudan, Igor, Sabanayagam, Charumathi, Salomaa, Veikko, Schneiderman, Neil, Schöttker, Ben, Sims, Mario, Snieder, Harold, Stark, Klaus J., Stefansson, Kari, Stocker, Hannah, Stumvoll, Michael, Sulem, Patrick, Sveinbjornsson, Gardar, Svensson, Per O., Tai, E-Shyong, Taylor, Kent D., Tayo, Bamidele O., Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H. L., Thomas, Laurent F., Tremblay, Johanne, Tönjes, Anke, van der Most, Peter J., Vitart, Veronique, Völker, Uwe, Wang, Ya Xing, Wang, Chaolong, Wei, Wen Bin, Whitfield, John B., Wild, Sarah H., Wilson, James F., Winkler, Thomas W., Wong, Tien-Yin, Woodward, Mark, Sim, Xueling, Chu, Audrey Y., Feitosa, Mary F., Thorsteinsdottir, Unnur, Hung, Adriana M., Teumer, Alexander, Franceschini, Nora, Parsa, Afshin, Köttgen, Anna, Schlosser, Pascal, and Pattaro, Cristian

Published
2024
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11. Distinct genetic liability profiles define clinically relevant patient strata across common diseases

Author

Lucia Trastulla, Georgii Dolgalev, Sylvain Moser, Laura T. Jiménez-Barrón, Till F. M. Andlauer, Moritz von Scheidt, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Monika Budde, Urs Heilbronner, Sergi Papiol, Alexander Teumer, Georg Homuth, Henry Völzke, Marcus Dörr, Peter Falkai, Thomas G. Schulze, Julien Gagneur, Francesco Iorio, Bertram Müller-Myhsok, Heribert Schunkert, and Michael J. Ziller

Subjects
Science
Abstract

Abstract Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.

Published
2024
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12. New insights into the hypothalamic–pituitary– thyroid axis: a transcriptome- and proteome-wide association study

Author

Sara Monteiro-Martins, Rosalie B T M Sterenborg, Oleg Borisov, Nora Scherer, Yurong Cheng, Marco Medici, Anna Köttgen, and Alexander Teumer

Subjects
twas, pwas, hpt axis, thyroid, hypothalamus, pituitary, tsh, ft4, colocalization, metabolism, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Introduction: Thyroid hormones have systemic effects on the human body and play a key role in the development and function of virtually all tissues. They are regulated via the hypothalamic–pituitary–thyroid (HPT) axis and have a heritable component. Using genetic information, we applied tissue-specific transcriptome-wide association studies (TWAS) and plasma proteome-wide association studies (PWAS) to elucidate gene products related to thyrotropin (TSH) and free thyroxine (FT4) levels. Results: TWAS identified 297 and 113 transcripts associated with TSH and FT4 levels, respectively (25 shared), including transcripts not identified by genome-wide association studies (GWAS) of these traits, demonstrating the increased power of this approach. Testing for genetic colocalization revealed a shared genetic basis of 158 transcripts with TSH and 45 transcripts with FT4, including independent, FT4-associated genetic signals within the CAPZB locus that were differentially associated with CAPZB expression in different tissues. PWAS identified 18 and ten proteins associated with TSH and FT4, respectively (HEXIM1 and QSOX2 with both). Among these, the cognate genes of five TSH- and 7 FT4-associated proteins mapped outside significant GWAS loci. Colocalization was observed for five plasma proteins each with TSH and FT4. There were ten TSH and one FT4-related gene(s) significant in both TWAS and PWAS. Of these, ANXA5 expression and plasma annexin A5 levels were inversely associated with TSH (PWAS: P = 1.18 × 10−13, TWAS: P = 7.61 × 10−12 (whole blood), P = 6.40 × 10−13 (hypothalamus), P = 1.57 × 10−15 (pituitary), P = 4.27 × 10−15 (thyroid)), supported by colocalizations. Conclusion: Our analyses revealed new thyroid function-associated genes and prioritized candidates in known GWAS loci, contributing to a better understanding of transcriptional regulation and protein levels relevant to thyroid function.

Published
2024
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13. Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

Author

Yang, Yunju, Knol, Maria J, Wang, Ruiqi, Mishra, Aniket, Liu, Dan, Luciano, Michelle, Teumer, Alexander, Armstrong, Nicola, Bis, Joshua C, Jhun, Min A, Li, Shuo, Adams, Hieab HH, Aziz, Nasir Ahmad, Bastin, Mark E, Bourgey, Mathieu, Brody, Jennifer A, Frenzel, Stefan, Gottesman, Rebecca F, Hosten, Norbert, Hou, Lifang, Kardia, Sharon LR, Lohner, Valerie, Marquis, Pascale, Maniega, Susana Muñoz, Satizabal, Claudia L, Sorond, Farzaneh A, Valdés Hernández, Maria C, van Duijn, Cornelia M, Vernooij, Meike W, Wittfeld, Katharina, Yang, Qiong, Zhao, Wei, Boerwinkle, Eric, Levy, Daniel, Deary, Ian J, Jiang, Jiyang, Mather, Karen A, Mosley, Thomas H, Psaty, Bruce M, Sachdev, Perminder S, Smith, Jennifer A, Sotoodehnia, Nona, DeCarli, Charles S, Breteler, Monique MB, Ikram, M Arfan, Grabe, Hans J, Wardlaw, Joanna, Longstreth, WT, Launer, Lenore J, Seshadri, Sudha, Debette, Stephanie, and Fornage, Myriam

Subjects
Health Sciences, Genetics, Aging, Brain Disorders, Neurosciences, Human Genome, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Middle Aged, Humans, Aged, White Matter, Genome-Wide Association Study, Brain, DNA Methylation, Magnetic Resonance Imaging, Epigenesis, Genetic, Protein-Arginine N-Methyltransferases, Repressor Proteins, epigenome-wide association study, white matter hyperintensities, cerebral small vessel disease, integrative cross-omics analysis, blood-brain barrier dysfunction, blood–brain barrier dysfunction, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

Published
2023

14. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Author

Lahti, Jari, Tuominen, Samuli, Yang, Qiong, Pergola, Giulio, Ahmad, Shahzad, Amin, Najaf, Armstrong, Nicola J, Beiser, Alexa, Bey, Katharina, Bis, Joshua C, Boerwinkle, Eric, Bressler, Jan, Campbell, Archie, Campbell, Harry, Chen, Qiang, Corley, Janie, Cox, Simon R, Davies, Gail, De Jager, Philip L, Derks, Eske M, Faul, Jessica D, Fitzpatrick, Annette L, Fohner, Alison E, Ford, Ian, Fornage, Myriam, Gerring, Zachary, Grabe, Hans J, Grodstein, Francine, Gudnason, Vilmundur, Simonsick, Eleanor, Holliday, Elizabeth G, Joshi, Peter K, Kajantie, Eero, Kaprio, Jaakko, Karell, Pauliina, Kleineidam, Luca, Knol, Maria J, Kochan, Nicole A, Kwok, John B, Leber, Markus, Lam, Max, Lee, Teresa, Li, Shuo, Loukola, Anu, Luck, Tobias, Marioni, Riccardo E, Mather, Karen A, Medland, Sarah, Mirza, Saira S, Nalls, Mike A, Nho, Kwangsik, O’Donnell, Adrienne, Oldmeadow, Christopher, Painter, Jodie, Pattie, Alison, Reppermund, Simone, Risacher, Shannon L, Rose, Richard J, Sadashivaiah, Vijay, Scholz, Markus, Satizabal, Claudia L, Schofield, Peter W, Schraut, Katharina E, Scott, Rodney J, Simino, Jeannette, Smith, Albert V, Smith, Jennifer A, Stott, David J, Surakka, Ida, Teumer, Alexander, Thalamuthu, Anbupalam, Trompet, Stella, Turner, Stephen T, van der Lee, Sven J, Villringer, Arno, Völker, Uwe, Wilson, Robert S, Wittfeld, Katharina, Vuoksimaa, Eero, Xia, Rui, Yaffe, Kristine, Yu, Lei, Zare, Habil, Zhao, Wei, Ames, David, Attia, John, Bennett, David A, Brodaty, Henry, Chasman, Daniel I, Goldman, Aaron L, Hayward, Caroline, Ikram, M Arfan, Jukema, J Wouter, Kardia, Sharon LR, Lencz, Todd, Loeffler, Markus, Mattay, Venkata S, Palotie, Aarno, Psaty, Bruce M, and Ramirez, Alfredo

Subjects
Biological Psychology, Psychology, Genetics, Human Genome, Dementia, Behavioral and Social Science, Brain Disorders, Acquired Cognitive Impairment, Mental Health, Biotechnology, Aging, Clinical Research, Neurosciences, Basic Behavioral and Social Science, Aetiology, 2.1 Biological and endogenous factors, Neurological, Mental health, Memory, Short-Term, Learning, Verbal Learning, Multifactorial Inheritance, Brain, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Published
2022

15. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.

Author

Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas, Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn, Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer, Bartz, Traci, Bentley, Amy, Bielak, Lawrence, Chong, Mike, Chu, Audrey, Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole, Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary, Gieger, Christian, Graff, Mariaelisa, Hall, Leanne, Haller, Toomas, Hartwig, Fernando, Hillis, David, Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne, Johansson, Åsa, Jørgensen, Anja, Kaakinen, Marika, Karlsson, Robert, Kerr, Kathleen, Kim, Boram, Koolhaas, Chantal, Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope, Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine, Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca, Rivera, Natalia, Robiou-du-Pont, Sebastien, Schraut, Katharina, Schulz, Christina-Alexandra, Stringham, Heather, Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter, Vanmunster, Mathias, van Rooij, Frank, van Vliet-Ostaptchouk, Jana, Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie, Baumeister, Sebastian, Beilby, John, Blangero, John, Boomsma, Dorret, Brage, Soren, Braund, Peter, Brody, Jennifer, Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John, Collins, Francis, Cupples, L, Esko, Tõnu, Enroth, Stefan, Faul, Jessica, Fernandez-Rhodes, Lindsay, Fohner, Alison, Franco, Oscar, Galesloot, Tessel, Gordon, Scott, Grarup, Niels, Hartman, Catharina, Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter, Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas, Koh, Woon-Puay, and Kolcic, Ivana

Subjects
Actinin, Cross-Sectional Studies, Exercise, Genome-Wide Association Study, Humans, Leisure Activities, Sedentary Behavior
Abstract

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Published
2022

16. The role of thyroid function in borderline personality disorder and schizophrenia: a Mendelian Randomisation study

Author

Oladapo Babajide, Alisa D. Kjaergaard, Weichen Deng, Aleksander Kuś, Rosalie B. T. M. Sterenborg, Bjørn Olav Åsvold, Stephen Burgess, Alexander Teumer, Marco Medici, German Borderline Genomics Consortium, Christina Ellervik, Bass Nick, Panos Deloukas, and Eirini Marouli

Subjects
Schizophrenia, Borderline Personality Disorder, Mendelian Randomisation, Thyroid function, TSH, FT4, Psychiatry, RC435-571
Abstract

Abstract Background Genome-wide association studies have reported a genetic overlap between borderline personality disorder (BPD) and schizophrenia (SCZ). Epidemiologically, the direction and causality of the association between thyroid function and risk of BPD and SCZ are unclear. We aim to test whether genetically predicted variations in TSH and FT4 levels or hypothyroidism are associated with the risk of BPD and SCZ. Methods We employed Mendelian Randomisation (MR) analyses using genetic instruments associated with TSH and FT4 levels as well as hypothyroidism to examine the effects of genetically predicted thyroid function on BPD and SCZ risk. Bidirectional MR analyses were employed to investigate a potential reverse causal association. Results Genetically predicted higher FT4 was not associated with the risk of BPD (OR: 1.18; P = 0.60, IVW) or the risk of SCZ (OR: 0.93; P = 0.19, IVW). Genetically predicted higher TSH was not associated with the risk of BPD (OR: 1.11; P = 0.51, IVW) or SCZ (OR: 0.98, P = 0.55, IVW). Genetically predicted hypothyroidism was not associated with BPD or SCZ. We found no evidence for a reverse causal effect between BPD or SCZ on thyroid function. Conclusions We report evidence for a null association between genetically predicted FT4, TSH or hypothyroidism with BPD or SCZ risk. There was no evidence for reverse causality.

Published
2024
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17. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author

Rosalie B. T. M. Sterenborg, Inga Steinbrenner, Yong Li, Melissa N. Bujnis, Tatsuhiko Naito, Eirini Marouli, Tessel E. Galesloot, Oladapo Babajide, Laura Andreasen, Arne Astrup, Bjørn Olav Åsvold, Stefania Bandinelli, Marian Beekman, John P. Beilby, Jette Bork-Jensen, Thibaud Boutin, Jennifer A. Brody, Suzanne J. Brown, Ben Brumpton, Purdey J. Campbell, Anne R. Cappola, Graziano Ceresini, Layal Chaker, Daniel I. Chasman, Maria Pina Concas, Rodrigo Coutinho de Almeida, Simone M. Cross, Francesco Cucca, Ian J. Deary, Alisa Devedzic Kjaergaard, Justin B. Echouffo Tcheugui, Christina Ellervik, Johan G. Eriksson, Luigi Ferrucci, Jan Freudenberg, GHS DiscovEHR, Regeneron Genetics Center, Christian Fuchsberger, Christian Gieger, Franco Giulianini, Martin Gögele, Sarah E. Graham, Niels Grarup, Ivana Gunjača, Torben Hansen, Barbara N. Harding, Sarah E. Harris, Stig Haunsø, Caroline Hayward, Jennie Hui, Till Ittermann, J. Wouter Jukema, Eero Kajantie, Jørgen K. Kanters, Line L. Kårhus, Lambertus A. L. M. Kiemeney, Margreet Kloppenburg, Brigitte Kühnel, Jari Lahti, Claudia Langenberg, Bruno Lapauw, Graham Leese, Shuo Li, David C. M. Liewald, Allan Linneberg, Jesus V. T. Lominchar, Jian’an Luan, Nicholas G. Martin, Antonela Matana, Marcel E. Meima, Thomas Meitinger, Ingrid Meulenbelt, Braxton D. Mitchell, Line T. Møllehave, Samia Mora, Silvia Naitza, Matthias Nauck, Romana T. Netea-Maier, Raymond Noordam, Casia Nursyifa, Yukinori Okada, Stefano Onano, Areti Papadopoulou, Colin N. A. Palmer, Cristian Pattaro, Oluf Pedersen, Annette Peters, Maik Pietzner, Ozren Polašek, Peter P. Pramstaller, Bruce M. Psaty, Ante Punda, Debashree Ray, Paul Redmond, J. Brent Richards, Paul M. Ridker, Tom C. Russ, Kathleen A. Ryan, Morten Salling Olesen, Ulla T. Schultheiss, Elizabeth Selvin, Moneeza K. Siddiqui, Carlo Sidore, P. Eline Slagboom, Thorkild I. A. Sørensen, Enrique Soto-Pedre, Tim D. Spector, Beatrice Spedicati, Sundararajan Srinivasan, John M. Starr, David J. Stott, Toshiko Tanaka, Vesela Torlak, Stella Trompet, Johanna Tuhkanen, André G. Uitterlinden, Erik B. van den Akker, Tibbert van den Eynde, Melanie M. van der Klauw, Diana van Heemst, Charlotte Verroken, W. Edward Visser, Dina Vojinovic, Henry Völzke, Melanie Waldenberger, John P. Walsh, Nicholas J. Wareham, Stefan Weiss, Cristen J. Willer, Scott G. Wilson, Bruce H. R. Wolffenbuttel, Hanneke J. C. M. Wouters, Margaret J. Wright, Qiong Yang, Tatijana Zemunik, Wei Zhou, Gu Zhu, Sebastian Zöllner, Johannes W. A. Smit, Robin P. Peeters, Anna Köttgen, Alexander Teumer, and Marco Medici

Subjects
Science
Abstract

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Published
2024
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18. Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

Author

Hao Mei, Jeannette Simino, Lianna Li, Fan Jiang, Joshua C. Bis, Gail Davies, W David Hill, Charley Xia, Vilmundur Gudnason, Qiong Yang, Jari Lahti, Jennifer A. Smith, Mirna Kirin, Philip De Jager, Nicola J. Armstrong, Mohsen Ghanbari, Ivana Kolcic, Christopher Moran, Alexander Teumer, Murali Sargurupremraj, Shamsed Mahmud, Myriam Fornage, Wei Zhao, Claudia L. Satizabal, Ozren Polasek, Katri Räikkönen, David C. Liewald, Georg Homuth, Michele Callisaya, Karen A. Mather, B. Gwen Windham, Tatijana Zemunik, Aarno Palotie, Alison Pattie, Sandra van der Auwera, Anbupalam Thalamuthu, David S. Knopman, Igor Rudan, John M. Starr, Katharina Wittfeld, Nicole A. Kochan, Michael E. Griswold, Veronique Vitart, Henry Brodaty, Rebecca Gottesman, Simon R. Cox, Bruce M. Psaty, Eric Boerwinkle, Daniel I. Chasman, Francine Grodstein, Perminder S. Sachdev, Velandai Srikanth, Caroline Hayward, James F. Wilson, Johan G. Eriksson, Sharon L. R. Kardia, Hans J. Grabe, David A. Bennett, M. Arfan Ikram, Ian J. Deary, Cornelia M. van Duijn, Lenore Launer, Annette L. Fitzpatrick, Sudha Seshadri, Jan Bressler, Stephanie Debette, and Thomas H. Mosley

Subjects
Genome-wide association study, Memory, Expression, Immunity, Multi-omics, Delayed recall, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. Methods We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. Results The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. Conclusions VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

Published
2024
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19. X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Author

Markus Scholz, Katrin Horn, Janne Pott, Matthias Wuttke, Andreas Kühnapfel, M. Kamal Nasr, Holger Kirsten, Yong Li, Anselm Hoppmann, Mathias Gorski, Sahar Ghasemi, Man Li, Adrienne Tin, Jin-Fang Chai, Massimiliano Cocca, Judy Wang, Teresa Nutile, Masato Akiyama, Bjørn Olav Åsvold, Nisha Bansal, Mary L. Biggs, Thibaud Boutin, Hermann Brenner, Ben Brumpton, Ralph Burkhardt, Jianwen Cai, Archie Campbell, Harry Campbell, John Chalmers, Daniel I. Chasman, Miao Ling Chee, Miao Li Chee, Xu Chen, Ching-Yu Cheng, Renata Cifkova, Martha Daviglus, Graciela Delgado, Katalin Dittrich, Todd L. Edwards, Karlhans Endlich, J. Michael Gaziano, Ayush Giri, Franco Giulianini, Scott D. Gordon, Daniel F. Gudbjartsson, Stein Hallan, Pavel Hamet, Catharina A. Hartman, Caroline Hayward, Iris M. Heid, Jacklyn N. Hellwege, Bernd Holleczek, Hilma Holm, Nina Hutri-Kähönen, Kristian Hveem, Berend Isermann, Jost B. Jonas, Peter K. Joshi, Yoichiro Kamatani, Masahiro Kanai, Mika Kastarinen, Chiea Chuen Khor, Wieland Kiess, Marcus E. Kleber, Antje Körner, Peter Kovacs, Alena Krajcoviechova, Holly Kramer, Bernhard K. Krämer, Mikko Kuokkanen, Mika Kähönen, Leslie A. Lange, James P. Lash, Terho Lehtimäki, Hengtong Li, Bridget M. Lin, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Patrik K. E. Magnusson, Nicholas G. Martin, Koichi Matsuda, Yuri Milaneschi, Pashupati P. Mishra, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Winfried März, Matthias Nauck, Kjell Nikus, Ilja M. Nolte, Raymond Noordam, Yukinori Okada, Isleifur Olafsson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Markus Perola, Nicola Pirastu, Ozren Polasek, David J. Porteous, Tanja Poulain, Bruce M. Psaty, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Humaira Rasheed, Dermot F. Reilly, Kenneth M. Rice, Anne Richmond, Paul M. Ridker, Jerome I. Rotter, Igor Rudan, Charumathi Sabanayagam, Veikko Salomaa, Neil Schneiderman, Ben Schöttker, Mario Sims, Harold Snieder, Klaus J. Stark, Kari Stefansson, Hannah Stocker, Michael Stumvoll, Patrick Sulem, Gardar Sveinbjornsson, Per O. Svensson, E-Shyong Tai, Kent D. Taylor, Bamidele O. Tayo, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Laurent F. Thomas, Johanne Tremblay, Anke Tönjes, Peter J. van der Most, Veronique Vitart, Uwe Völker, Ya Xing Wang, Chaolong Wang, Wen Bin Wei, John B. Whitfield, Sarah H. Wild, James F. Wilson, Thomas W. Winkler, Tien-Yin Wong, Mark Woodward, Xueling Sim, Audrey Y. Chu, Mary F. Feitosa, Unnur Thorsteinsdottir, Adriana M. Hung, Alexander Teumer, Nora Franceschini, Afshin Parsa, Anna Köttgen, Pascal Schlosser, and Cristian Pattaro

Subjects
Science
Abstract

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Published
2024
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21. Ultrasound-Guided Venous Puncture Reduces Groin Complications in Electrophysiological Procedures

Author

Yannick Teumer, Daniel Eckart, Lyuboslav Katov, Markus Graf, Carlo Bothner, Wolfgang Rottbauer, and Karolina Weinmann-Emhardt

Subjects
cardiology, electrophysiology, ultrasound, venipuncture, vascular access complication, bleeding, Biology (General), QH301-705.5
Abstract

Background: In electrophysiological procedures, multiple punctures on the femoral vein can be necessary depending on the number of catheters required. The femoral vein is typically located indirectly by using its anatomical relationship to the artery as a reference. However, this conventional approach can lead to significant complications, including bleeding, peri-interventional transfusion, pseudoaneurysms, or arteriovenous fistulas. Despite these risks, there is limited evidence comparing the safety of ultrasound-guided venipuncture versus the conventional technique in electrophysiological procedures. Objective: This study aimed to evaluate the impact of ultrasound-guided venipuncture on vascular access complications in electrophysiological procedures and to identify associated risk factors. Methods: In this single-center trial, patients scheduled for electrophysiological procedures at Ulm University Heart Center, Germany, were enrolled between November 2021 and October 2023. Venipuncture in the groin was performed using either the conventional or an ultrasound-guided approach. The primary composite endpoint was defined as peri-interventional major vascular access complications (Bleeding Academic Research Consortium (BARC) ≥2 bleeding, pseudoaneurysms, arteriovenous fistulas, and peri-interventional transfusion) and minor complications (BARC 1). Results: A total of 1370 patients were included: 749 in the conventional group and 621 in the ultrasound group. The primary endpoint was achieved in 19.2% of the conventional group and 12.1% of the ultrasound group (p < 0.001). An increased sheath diameter and a higher number of venous accesses were identified as risk factors for the primary endpoint. Conclusions: Ultrasound guidance for venous groin puncture in electrophysiological procedures reduces access-related complications, supporting its use with careful attention to sheath size and number.

Published
2024
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22. Left Atrial Low-Voltage Extent Predicts the Recurrence of Supraventricular Arrhythmias

Author

Yannick Teumer, Luca Gold, Lyuboslav Katov, Carlo Bothner, Wolfgang Rottbauer, and Karolina Weinmann-Emhardt

Subjects
left atrial cardiomyopathy, fibrosis, recurrence prediction, supraventricular tachycardia, low voltage, 3D mapping, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

The incidence of left atrial (LA) supraventricular arrhythmias is increasing. Even after LA ablation, recurrence of these tachycardias is common. MRI studies show that LA cardiomyopathy is a significant risk factor for recurrence and correlates with low voltage areas detected via 3D electroanatomic mapping (EAM). There are limited data on the impact of low voltage extent detected by EAM on recurrence-free survival. Voltage thresholds defining low voltage vary across different studies. This study aims to investigate the impact of the extent of low voltage areas in the LA on recurrence-free survival and to assess whether defining low voltage areas using thresholds of 0.5, 0.4, or 0.3 mV offers better predictive performance. Patients with atrial arrhythmia who underwent LA EAM at Ulm University Heart Center between September 2018 and September 2022 were included from the ATRIUM registry. ROC analysis determined the voltage threshold for predicting recurrence-free survival. Kaplan–Meier and logistic regression models adjusted for patient variables were used to analyze recurrence-free survival. Of 1089 screened patients, 108 met the inclusion criteria. ROC analysis indicated that a 0.4 mV threshold for low voltage provided the best predictive performance. Logistic regression showed a 1.039-fold increase in recurrence risk per percent increase in LA low voltage area (odds ratio = 1.039, 95% CI 1.014–1.064). Low voltage extent in EAM correlates with 1-year recurrence rate after ablation of left atrial supraventricular arrhythmias. The threshold of 0.4 mV is the most suitable for predicting recurrences of those examined.

Published
2024
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23. Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate

Author

Mishra, Aniket, Duplaà, Cécile, Vojinovic, Dina, Suzuki, Hideaki, Sargurupremraj, Muralidharan, Zilhão, Nuno R, Li, Shuo, Bartz, Traci M, Jian, Xueqiu, Zhao, Wei, Hofer, Edith, Wittfeld, Katharina, Harris, Sarah E, van der Auwera-Palitschka, Sandra, Luciano, Michelle, Bis, Joshua C, Adams, Hieab HH, Satizabal, Claudia L, Gottesman, Rebecca F, Gampawar, Piyush G, Bülow, Robin, Weiss, Stefan, Yu, Miao, Bastin, Mark E, Lopez, Oscar L, Vernooij, Meike W, Beiser, Alexa S, Völker, Uwe, Kacprowski, Tim, Soumare, Aicha, Smith, Jennifer A, Knopman, David S, Morris, Zoe, Zhu, Yicheng, Rotter, Jerome I, Dufouil, Carole, Hernández, Maria Valdés, Maniega, Susana Muñoz, Lathrop, Mark, Boerwinkle, Erik, Schmidt, Reinhold, Ihara, Masafumi, Mazoyer, Bernard, Yang, Qiong, Joutel, Anne, Tournier-Lasserve, Elizabeth, Launer, Lenore J, Deary, Ian J, Mosley, Thomas H, Amouyel, Philippe, DeCarli, Charles S, Psaty, Bruce M, Tzourio, Christophe, Kardia, Sharon LR, Grabe, Hans J, Teumer, Alexander, van Duijn, Cornelia M, Schmidt, Helena, Wardlaw, Joanna M, Ikram, M Arfan, Fornage, Myriam, Gudnason, Vilmundur, Seshadri, Sudha, Matthews, Paul M, Longstreth, William T, Couffinhal, Thierry, and Debette, Stephanie

Subjects
Epidemiology, Health Sciences, Acquired Cognitive Impairment, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Stroke, Neurosciences, Human Genome, Biotechnology, Clinical Research, Dementia, Aging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Cardiovascular, Animals, Brain Ischemia, Cerebral Small Vessel Diseases, Endothelial Cells, Genome-Wide Association Study, Mice, cerebral small vessel disease, endothelial cells, GWAS, TRIM47, whole-exome association study, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Published
2022

24. Cortical similarities in psychiatric and mood disorders identified in federated VBM analysis via COINSTAC

Author

Rootes-Murdy, Kelly, Panta, Sandeep, Kelly, Ross, Romero, Javier, Quidé, Yann, Cairns, Murray J., Loughland, Carmel, Carr, Vaughan J., Catts, Stanley V., Jablensky, Assen, Green, Melissa J., Henskens, Frans, Kiltschewskij, Dylan, Michie, Patricia T., Mowry, Bryan, Pantelis, Christos, Rasser, Paul E., Reay, William R., Schall, Ulrich, Scott, Rodney J., Watkeys, Oliver J., Roberts, Gloria, Mitchell, Philip B., Fullerton, Janice M., Overs, Bronwyn J., Kikuchi, Masataka, Hashimoto, Ryota, Matsumoto, Junya, Fukunaga, Masaki, Sachdev, Perminder S., Brodaty, Henry, Wen, Wei, Jiang, Jiyang, Fani, Negar, Ely, Timothy D., Lorio, Adriana, Stevens, Jennifer S., Ressler, Kerry, Jovanovic, Tanja, van Rooij, Sanne J.H., Federmann, Lydia M., Jockwitz, Christiane, Teumer, Alexander, Forstner, Andreas J., Caspers, Svenja, Cichon, Sven, Plis, Sergey M., Sarwate, Anand D., and Calhoun, Vince D.

Published
2024
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25. Prioritization of Kidney Cell Types Highlights Myofibroblast Cells in Regulating Human Blood Pressure

Author

Evangelou, Evangelos, Warren, Helen R., Gao, He, Ntritsos, Georgios, Dimou, Niki, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G., Jackson, Anne U., Li -Gao, Ruifang, Lin, Wei -Yu, Luan, Jian'an, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M., Zhao, Jing -Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S.F., Farrall, Martin, Menni, Cristina, Morris, Andrew D., Noordam, Raymond, Paré, Guillaume, Poulter, Neil R., Shields, Denis C., Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E., Ayers, Kristin L., Barbieri, Caterina M., Batini, Chiara, Bis, Joshua C., Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I., Bottinger, Erwin P., Braund, Peter S., Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C., Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Francis, Cordell, Heather J., Davies, Gail, de Borst, Martin H., de Geus, Eco J., Deary, Ian J., Deelen, Joris, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcus, Ehret, Georg B., Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A. Mesut, Ferreira, Teresa, Frånberg, Mattias, Franco, Oscar H., Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J., Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B., Harris, Sarah E., Hartman, Catharina A., Havulinna, Aki S., Hicks, Andrew A., Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E., Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo -Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D., Joshi, Peter K., Jousilahti, Pekka, Jukema, J. Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D., Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S., Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Maris, Larson, Marty, Launer, Lenore J., Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C.M., Lin, Li, Lind, Lars, Lindgren, Cecilia M., Liu, YongMei, Loos, Ruth J.F., Lopez, Lorna M., Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P., Morrison, Alanna C., Munson, Peter J., Nalls, Mike A., Nandakumar, Priyanka, Nelson, Christopher P., Niiranen, Teemu, Nolte, Ilja M., Nutile, Teresa, Oldehinkel, Albertine J., Oostra, Ben A., O'Reilly, Paul F., Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W.J.H., Perola, Markus, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P., Nguyen, Quang Tri, Raitakari, Olli T., Rettig, Rainer, Rice, Kenneth, Ridker, Paul M., Ried, Janina S., Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M., Rotter, Jerome I., Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F., Salomaa, Veikko, Samani, Nilesh J., Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V., Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M., Stott, David J., Strachan, David P., Strawbridge, Rona J., Sundström, Johan, Swertz, Morris A., Taylor, Kent D., Teumer, Alexander, Tobin, Martin D., Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G., Vaez, Ahmad, van der Most, Peter J., van Duijn, Cornelia M., Verwoert, Germaine C., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H., Willemsen, Gonneke, Wilson, James F., Wright, Alan F., Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R., Butterworth, Adam S., Chasman, Daniel I., Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M.M., Laakso, Markku, Lakatta, Edward G., Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O., Palmer, Colin N.A., Risch, Lorenz, Scott, Robert A., Scott, Rodney J., Sever, Peter, Spector, Tim D., van der Harst, Pim, Wareham, Nicholas J., Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B., Newton-Cheh, Christopher, Brown, Morris J., Metspalu, Andres, Psaty, Bruce M., Wain, Louise V., Elliott, Paul, Caulfield, Mark J., Ganji-Arjenaki, Mahboube, Kamali, Zoha, Sardari, Soroush, and de Borst, Martin

Published
2024
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28. Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer’s Disease in Predominantly Middle-Aged Adults

Author

Wittfeld, Katharina, Raman, Mekala R, Conner, Sarah C, Aslam, Asra, Teumer, Alexander, Nauck, Matthias, Hosten, Norbert, Habes, Mohamad, DeCarli, Charles, Vasan, Ramachandran S, Beiser, Alexa S, Himali, Jayandra J, Seshadri, Sudha, Grabe, Hans J, and Satizabal, Claudia L

Subjects
Paediatrics, Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Brain Disorders, Neurodegenerative, Aging, Cardiovascular, Alzheimer's Disease, Dementia, Cerebrovascular, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, 2.1 Biological and endogenous factors, Neurological, Adult, Alzheimer Disease, Biomarkers, C-Reactive Protein, Female, Humans, Inflammation, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Magnetic Resonance Imaging, Male, Middle Aged, Alzheimer's disease endophenotype, C-reactive protein, cohort study, epidemiology, hippocampus, insulin-like growth factor, neuroimaging, white matter hyperintensity, Alzheimer’s disease endophenotype, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundInsulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults.ObjectiveTo investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation.MethodsWe included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons.ResultsMeta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations

Published
2022

29. Investigation of the Interplay between Circulating Lipids and IGF-I and Relevance to Breast Cancer Risk: An Observational and Mendelian Randomization Study

Author

Tan, Vanessa Y, Bull, Caroline J, Biernacka, Kalina M, Teumer, Alexander, Richardson, Tom G, Sanderson, Eleanor, Corbin, Laura J, Dudding, Tom, Qi, Qibin, Kaplan, Robert C, Rotter, Jerome I, Friedrich, Nele, Völker, Uwe, Mayerle, Julia, Perks, Claire M, Holly, Jeff MP, and Timpson, Nicholas J

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Breast Cancer, Cardiovascular, Atherosclerosis, Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Causality, Cholesterol, HDL, Cholesterol, LDL, Cross-Sectional Studies, Female, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor I, Mendelian Randomization Analysis, Triglycerides, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundCirculating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer. Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to breast cancer overlap is unclear.MethodsMendelian randomization (MR) was conducted to estimate the relationship between lipids or IGF-I and breast cancer risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol, LDL-C; high-density lipoprotein cholesterol, HDL-C; triglycerides, TGs), IGF-I and breast cancer from GLGC/UKBB (N = 239,119), CHARGE/UKBB (N = 252,547), and Breast Cancer Association Consortium (N = 247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bi-directional relationship between lipids and IGF-I in SHIP (N = 3,812) and UKBB (N = 422,389), and using genetic summary statistics from GLGC (N = 188,577) and CHARGE/UKBB (N = 469,872).ResultsIn multivariable MR (MVMR) analyses, the OR for breast cancer per 1-SD increase in HDL-C and TG was 1.08 [95% confidence interval (CI), 1.04-1.13] and 0.94 (95% CI, 0.89-0.98), respectively. The OR for breast cancer per 1-SD increase in IGF-I was 1.09 (95% CI, 1.04-1.15). MR analyses suggested a bi-directional TG-IGF-I relationship (TG-IGF-I β per 1-SD: -0.13; 95% CI, -0.23 to -0.04; and IGF-I-TG β per 1-SD: -0.11; 95% CI, -0.18 to -0.05). There was little evidence for a causal relationship between HDL-C and LDL-C with IGF-I. In MVMR analyses, associations of TG or IGF-I with breast cancer were robust to adjustment for IGF-I or TG, respectively.ConclusionsOur findings suggest a causal role of HDL-C, TG, and IGF-I in breast cancer. Observational and MR analyses support an interplay between IGF-I and TG; however, MVMR estimates suggest that TG and IGF-I may act independently to influence breast cancer.ImpactOur findings should be considered in the development of prevention strategies for breast cancer, where interventions are known to modify circulating lipids and IGF-I.

Published
2021

30. Quantitative Analysis of Chlorogenic Acid during Coffee Roasting via Raman Spectroscopy

Author

Deborah Herdt, Tobias Teumer, Shaun Paul Keck, Thomas Kunz, Victoria Schiwek, Sarah Kühnemuth, Frank-Jürgen Methner, and Matthias Rädle

Subjects
Raman spectroscopy, chlorogenic acid, coffee roasting, degree of roasting, quality control, HPLC-DAD, Biochemistry, QD415-436
Abstract

Tracking coffee roasting at an industrial scale for quality control is challenging. Bean color is a practical gauge for monitoring and regulating the process but only occurs before and after the process. This study highlights the feasibility of monitoring the process throughout using Raman spectroscopy. Strecker degradation and the Maillard reaction contribute to various aromatic compounds that can serve as markers in quality monitoring. Among these are chlorogenic acids (CGAs), recognized as pivotal factors determining the desired aroma. Here, drum and fluidized bed roaster processes were monitored, capitalizing on the chemical alterations induced by high temperatures (140–200 °C), particularly through the Maillard reaction. These chemical changes manifest in the scattered light signal. For real-time monitoring, Raman spectra were taken every 10 ms in selected ranges, with an average calculated every second. Utilizing a calibration matrix from a High-Pressure Liquid Chromatography (HPLC) method, CGA concentration becomes the control variable for assessing roasting progress. This study reveals the potential of Raman spectroscopy for tracking CGA during roasting. It establishes a correlation between inelastic scattered light and CGA validated through laboratory measurements and fixed roasting conditions, resulting in a theoretical CGA concentration that can be used as a process termination criterion.

Published
2024
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31. Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ)

Author

Fromme, Malin, Hamesch, Karim, Schneider, Carolin V., Mandorfer, Mattias, Pons, Monica, Thorhauge, Katrine H., Pereira, Vitor, Sperl, Jan, Frankova, Sona, Reichert, Matthias C., Benini, Federica, Burbaum, Barbara, Kleinjans, Moritz, Amzou, Samira, Rademacher, Laura, Bewersdorf, Lisa, Verbeek, Jef, Nevens, Frederik, Genesca, Joan, Miravitlles, Marc, Nuñez, Alexa, Schaefer, Benedikt, Zoller, Heinz, Janciauskiene, Sabina, Waern, Johan, Oliveira, António, Maia, Luís, Simões, Carolina, Mahadeva, Ravi, Fraughen, Daniel D., Trauner, Michael, Krag, Aleksander, Lammert, Frank, Bals, Robert, Gaisa, Nadine T., Aigner, Elmar, Griffiths, William J., Denk, Helmut, Teumer, Alexander, McElvaney, Noel G., Turner, Alice M., Trautwein, Christian, and Strnad, Pavel

Published
2024
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32. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

Author

Mathieson, Iain, Day, Felix R., Barban, Nicola, Tropf, Felix C., Brazel, David M., Vaez, Ahmad, van Zuydam, Natalie, Bitarello, Bárbara D., Gardner, Eugene J., Akimova, Evelina T., Azad, Ajuna, Bergmann, Sven, Bielak, Lawrence F., Boomsma, Dorret I., Bosak, Kristina, Brumat, Marco, Buring, Julie E., Cesarini, David, Chasman, Daniel I., Chavarro, Jorge E., Cocca, Massimiliano, Concas, Maria Pina, Davey Smith, George, Davies, Gail, Deary, Ian J., Esko, Tõnu, Faul, Jessica D., Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J., Gelemanovic, Andrea, de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P., Hayward, Caroline, He, Chunyan, van Heemst, Diana, Hill, W. David, Hoffmann, Eva R., Homuth, Georg, Hottenga, Jouke Jan, Huang, Hongyang, Hyppӧnen, Elina, Ikram, M. Arfan, Jansen, Rick, Johannesson, Magnus, Kamali, Zoha, Kardia, Sharon L. R., Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Liew, Gerald, Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, Medland, Sarah E., Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Milani, Lili, Missmer, Stacey A., Mitchell, Paul, Møllegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter J., de Mutsert, Renée, Nauck, Matthias, Nolte, Ilja M., Noordam, Raymond, Penninx, Brenda W. J. H., Peters, Annette, Peyser, Patricia A., Polašek, Ozren, Power, Chris, Pribisalic, Ajka, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Shukla, Vallari, Smith, Jennifer A., Stankovic, Stasa, Stefánsson, Kári, Stöckl, Doris, Strauch, Konstantin, Swertz, Morris A., Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Uitterlinden, André G., Waldenberger, Melanie, Wareham, Nicholas J., Weir, David R., Willemsen, Gonneke, Zhao, Jing Hau, Zhao, Wei, Zhao, Yajie, Snieder, Harold, den Hoed, Marcel, Ong, Ken K., Mills, Melinda C., and Perry, John R. B.

Published
2023
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33. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Author

Duperron, Marie-Gabrielle, Knol, Maria J., Le Grand, Quentin, Evans, Tavia E., Mishra, Aniket, Tsuchida, Ami, Roshchupkin, Gennady, Konuma, Takahiro, Trégouët, David-Alexandre, Romero, Jose Rafael, Frenzel, Stefan, Luciano, Michelle, Hofer, Edith, Bourgey, Mathieu, Dueker, Nicole D., Delgado, Pilar, Hilal, Saima, Tankard, Rick M., Dubost, Florian, Shin, Jean, Saba, Yasaman, Armstrong, Nicola J., Bordes, Constance, Bastin, Mark E., Beiser, Alexa, Brodaty, Henry, Bülow, Robin, Carrera, Caty, Chen, Christopher, Cheng, Ching-Yu, Deary, Ian J., Gampawar, Piyush G., Himali, Jayandra J., Jiang, Jiyang, Kawaguchi, Takahisa, Li, Shuo, Macalli, Melissa, Marquis, Pascale, Morris, Zoe, Muñoz Maniega, Susana, Miyamoto, Susumu, Okawa, Masakazu, Paradise, Matthew, Parva, Pedram, Rundek, Tatjana, Sargurupremraj, Muralidharan, Schilling, Sabrina, Setoh, Kazuya, Soukarieh, Omar, Tabara, Yasuharu, Teumer, Alexander, Thalamuthu, Anbupalam, Trollor, Julian N., Valdés Hernández, Maria C., Vernooij, Meike W., Völker, Uwe, Wittfeld, Katharina, Wong, Tien Yin, Wright, Margaret J., Zhang, Junyi, Zhao, Wanting, Zhu, Yi-Cheng, Schmidt, Helena, Sachdev, Perminder S., Wen, Wei, Yoshida, Kazumichi, Joutel, Anne, Satizabal, Claudia L., Sacco, Ralph L., Bourque, Guillaume, Lathrop, Mark, Paus, Tomas, Fernandez-Cadenas, Israel, Yang, Qiong, Mazoyer, Bernard, Boutinaud, Philippe, Okada, Yukinori, Grabe, Hans J., Mather, Karen A., Schmidt, Reinhold, Joliot, Marc, Ikram, M. Arfan, Matsuda, Fumihiko, Tzourio, Christophe, Wardlaw, Joanna M., Seshadri, Sudha, Adams, Hieab H. H., and Debette, Stéphanie

Published
2023
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34. Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family

Author

Zhongli Chen, Robin P Peeters, Wesley Flach, Linda J de Rooij, Sena Yildiz, Alexander Teumer, Matthias Nauck, Rosalie B T M Sterenborg, Joost H W Rutten, Marco Medici, W Edward Visser, and Marcel E Meima

Subjects
thyroid hormone, transporter, solute carrier 22 family, thyroid hormone sulfate, organic anion transporter, oat3, oat4, oat7, probenecid, lesinurad, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Objective: Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters Methods: Uptake of 1 nM of iodothyronines or sulfated iodothyronines in COS1 cells expressing SLC22 proteins was performed. Results: We first tested 25 mouse (m) SLC22 proteins for TH uptake and fo und that the majority of the organic anion transporter (OAT) clade were capable of 3,3’,5-triiodothyronine and/or thyroxine (T4) transport. Based on phylogenetic tree analysis of the mouse and human (h) SLC22 family, we selected eight hSLC22s that grouped with the newly identified mouse TH transporters. Of thes e, four tested positive for uptake of one or more substrates, particularly hSLC22A11 showed robust (3-fold over control) uptake of T4. Uptake of sulfated iodothyronines was strongly (up to 17-fold) induced by some SLC22s, most notably SLC22A8, hSLC22A9, mSLC22A27 and mSLC22A29. Finally, the zebrafish orthologues of SLC22A6/8 drOat x and drSlc22a6l also transported almost all (sulfated) iodothyronines tested. The OAT inhibitors lesinurad and probenecid inhibited most SLC22 proteins. Conclusions: Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology.

Published
2023
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35. Mendelian randomization indicates causal effects of estradiol levels on kidney function in males

Author

M. Kamal Nasr, Claudia Schurmann, Erwin P. Böttinger, and Alexander Teumer

Subjects
glomerular filtration rate, steroids, albuminuria, genome-wide association study, causality, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

ContextChronic kidney disease (CKD) is a public health burden worldwide. Epidemiological studies observed an association between sex hormones, including estradiol, and kidney function.ObjectiveWe conducted a Mendelian randomization (MR) study to assess a possible causal effect of estradiol levels on kidney function in males and females.DesignWe performed a bidirectional two-sample MR using published genetic associations of serum levels of estradiol in men (n = 206,927) and women (n = 229,966), and of kidney traits represented by estimated glomerular filtration rate (eGFR, n = 567,460), urine albumin-to-creatinine ratio (UACR, n = 547,361), and CKD (n = 41,395 cases and n = 439,303 controls) using data obtained from the CKDGen Consortium. Additionally, we conducted a genome-wide association study using UK Biobank cohort study data (n = 11,798 men and n = 6,835 women) to identify novel genetic associations with levels of estradiol, and then used these variants as instruments in a one-sample MR.ResultsThe two-sample MR indicated that genetically predicted estradiol levels are significantly associated with eGFR in men (beta = 0.077; p = 5.2E-05). We identified a single locus at chromosome 14 associated with estradiol levels in men being significant in the one-sample MR on eGFR (beta = 0.199; p = 0.017). We revealed significant results with eGFR in postmenopausal women and with UACR in premenopausal women, which did not reach statistical significance in the sensitivity MR analyses. No causal effect of eGFR or UACR on estradiol levels was found.ConclusionsWe conclude that serum estradiol levels may have a causal effect on kidney function. Our MR results provide starting points for studies to develop therapeutic strategies to reduce kidney disease.

Published
2023
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37. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author

Gorski, Mathias, Jung, Bettina, Li, Yong, Matias-Garcia, Pamela R, Wuttke, Matthias, Coassin, Stefan, Thio, Chris HL, Kleber, Marcus E, Winkler, Thomas W, Wanner, Veronika, Chai, Jin-Fang, Chu, Audrey Y, Cocca, Massimiliano, Feitosa, Mary F, Ghasemi, Sahar, Hoppmann, Anselm, Horn, Katrin, Li, Man, Nutile, Teresa, Scholz, Markus, Sieber, Karsten B, Teumer, Alexander, Tin, Adrienne, Wang, Judy, Tayo, Bamidele O, Ahluwalia, Tarunveer S, Almgren, Peter, Bakker, Stephan JL, Banas, Bernhard, Bansal, Nisha, Biggs, Mary L, Boerwinkle, Eric, Bottinger, Erwin P, Brenner, Hermann, Carroll, Robert J, Chalmers, John, Chee, Miao-Li, Chee, Miao-Ling, Cheng, Ching-Yu, Coresh, Josef, de Borst, Martin H, Degenhardt, Frauke, Eckardt, Kai-Uwe, Endlich, Karlhans, Franke, Andre, Freitag-Wolf, Sandra, Gampawar, Piyush, Gansevoort, Ron T, Ghanbari, Mohsen, Gieger, Christian, Hamet, Pavel, Ho, Kevin, Hofer, Edith, Holleczek, Bernd, Foo, Valencia Hui Xian, Hutri-Kähönen, Nina, Hwang, Shih-Jen, Ikram, M Arfan, Josyula, Navya Shilpa, Kähönen, Mika, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Krämer, Bernhard K, Kühnel, Brigitte, Lange, Leslie A, Lehtimäki, Terho, Lieb, Wolfgang, Loos, Ruth JF, Lukas, Mary Ann, Lyytikäinen, Leo-Pekka, Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P, Mononen, Nina, Mychaleckyj, Josyf C, Nadkarni, Girish N, Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M, O’Donoghue, Michelle L, Orho-Melander, Marju, Pendergrass, Sarah A, Penninx, Brenda WJH, Preuss, Michael H, Psaty, Bruce M, Raffield, Laura M, Raitakari, Olli T, Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M, Rosenkranz, Alexander R, Rossing, Peter, Rotter, Jerome I, Sabanayagam, Charumathi, Schmidt, Helena, and Schmidt, Reinhold

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Human Genome, Kidney Disease, Rare Diseases, Genetics, Aetiology, 2.1 Biological and endogenous factors, Renal and urogenital, AMP-Activated Protein Kinases, Creatinine, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Protein Disulfide-Isomerases, United Kingdom, acute kidney injury, end-stage kidney disease, genome-wide association study, rapid eGFRcrea decline, Lifelines Cohort Study, Regeneron Genetics Center, Urology & Nephrology, Clinical sciences
Abstract

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Published
2021

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

Author

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

Subjects
Science
Abstract

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.

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

Author

Qile Dai, Geyu Zhou, Hongyu Zhao, Urmo Võsa, Lude Franke, Alexis Battle, Alexander Teumer, Terho Lehtimäki, Olli T. Raitakari, Tõnu Esko, eQTLGen Consortium, Michael P. Epstein, and Jingjing Yang

Subjects
Science
Abstract

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.

Published
2023
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40. Cerebral small vessel disease genomics and its implications across the lifespan.

Author

Sargurupremraj, Muralidharan, Suzuki, Hideaki, Jian, Xueqiu, Sarnowski, Chloé, Evans, Tavia E, Bis, Joshua C, Eiriksdottir, Gudny, Sakaue, Saori, Terzikhan, Natalie, Habes, Mohamad, Zhao, Wei, Armstrong, Nicola J, Hofer, Edith, Yanek, Lisa R, Hagenaars, Saskia P, Kumar, Rajan B, van den Akker, Erik B, McWhirter, Rebekah E, Trompet, Stella, Mishra, Aniket, Saba, Yasaman, Satizabal, Claudia L, Beaudet, Gregory, Petit, Laurent, Tsuchida, Ami, Zago, Laure, Schilling, Sabrina, Sigurdsson, Sigurdur, Gottesman, Rebecca F, Lewis, Cora E, Aggarwal, Neelum T, Lopez, Oscar L, Smith, Jennifer A, Valdés Hernández, Maria C, van der Grond, Jeroen, Wright, Margaret J, Knol, Maria J, Dörr, Marcus, Thomson, Russell J, Bordes, Constance, Le Grand, Quentin, Duperron, Marie-Gabrielle, Smith, Albert V, Knopman, David S, Schreiner, Pamela J, Evans, Denis A, Rotter, Jerome I, Beiser, Alexa S, Maniega, Susana Muñoz, Beekman, Marian, Trollor, Julian, Stott, David J, Vernooij, Meike W, Wittfeld, Katharina, Niessen, Wiro J, Soumaré, Aicha, Boerwinkle, Eric, Sidney, Stephen, Turner, Stephen T, Davies, Gail, Thalamuthu, Anbupalam, Völker, Uwe, van Buchem, Mark A, Bryan, R Nick, Dupuis, Josée, Bastin, Mark E, Ames, David, Teumer, Alexander, Amouyel, Philippe, Kwok, John B, Bülow, Robin, Deary, Ian J, Schofield, Peter R, Brodaty, Henry, Jiang, Jiyang, Tabara, Yasuharu, Setoh, Kazuya, Miyamoto, Susumu, Yoshida, Kazumichi, Nagata, Manabu, Kamatani, Yoichiro, Matsuda, Fumihiko, Psaty, Bruce M, Bennett, David A, De Jager, Philip L, Mosley, Thomas H, Sachdev, Perminder S, Schmidt, Reinhold, Warren, Helen R, Evangelou, Evangelos, Trégouët, David-Alexandre, International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC), Ikram, Mohammad A, Wen, Wei, DeCarli, Charles, Srikanth, Velandai K, Jukema, J Wouter, Slagboom, Eline P, and Kardia, Sharon LR

Subjects
International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium, Humans, Alzheimer Disease, Hypertension, Medical History Taking, Risk Assessment, Risk Factors, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Stroke, Genome-Wide Association Study, Young Adult, Diffusion Tensor Imaging, Genetic Loci, Mendelian Randomization Analysis, Cerebral Small Vessel Diseases, White Matter, and over
Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Published
2020

41. Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity

Author

Yaghootkar, Hanieh, Zhang, Yiying, Spracklen, Cassandra N, Karaderi, Tugce, Huang, Lam Opal, Bradfield, Jonathan, Schurmann, Claudia, Fine, Rebecca S, Preuss, Michael H, Kutalik, Zoltan, Wittemans, Laura BL, Lu, Yingchang, Metz, Sophia, Willems, Sara M, Li-Gao, Ruifang, Grarup, Niels, Wang, Shuai, Molnos, Sophie, Sandoval-Zárate, América A, Nalls, Mike A, Lange, Leslie A, Haesser, Jeffrey, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Feitosa, Mary F, Sitlani, Colleen M, Venturini, Cristina, Mahajan, Anubha, Kacprowski, Tim, Wang, Carol A, Chasman, Daniel I, Amin, Najaf, Broer, Linda, Robertson, Neil, Young, Kristin L, Allison, Matthew, Auer, Paul L, Blüher, Matthias, Borja, Judith B, Bork-Jensen, Jette, Carrasquilla, Germán D, Christofidou, Paraskevi, Demirkan, Ayse, Doege, Claudia A, Garcia, Melissa E, Graff, Mariaelisa, Guo, Kaiying, Hakonarson, Hakon, Hong, Jaeyoung, Ida Chen, Yii-Der, Jackson, Rebecca, Jakupović, Hermina, Jousilahti, Pekka, Justice, Anne E, Kähönen, Mika, Kizer, Jorge R, Kriebel, Jennifer, LeDuc, Charles A, Li, Jin, Lind, Lars, Luan, Jian'an, Mackey, David A, Mangino, Massimo, Männistö, Satu, Martin Carli, Jayne F, Medina-Gomez, Carolina, Mook-Kanamori, Dennis O, Morris, Andrew P, de Mutsert, Renée, Nauck, Matthias, Prokic, Ivana, Pennell, Craig E, Pradhan, Arund D, Psaty, Bruce M, Raitakari, Olli T, Scott, Robert A, Skaaby, Tea, Strauch, Konstantin, Taylor, Kent D, Teumer, Alexander, Uitterlinden, Andre G, Wu, Ying, Yao, Jie, Walker, Mark, North, Kari E, Kovacs, Peter, Ikram, M Arfan, van Duijn, Cornelia M, Ridker, Paul M, Lye, Stephen, Homuth, Georg, Ingelsson, Erik, Spector, Tim D, McKnight, Barbara, Province, Michael A, Lehtimäki, Terho, Adair, Linda S, Rotter, Jerome I, Reiner, Alexander P, and Wilson, James G

Subjects
Genetics, Nutrition, Prevention, Obesity, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Metabolic and endocrine, Cardiovascular, Stroke, Cancer, Adiposity, Gene Expression Regulation, Developmental, Genetic Variation, Genotype, Humans, Leptin, Models, Molecular, Protein Conformation, Racial Groups, Medical and Health Sciences, Endocrinology & Metabolism
Abstract

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

Published
2020

42. Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Author

Weng, Lu-Chen, Hall, Amelia Weber, Choi, Seung Hoan, Jurgens, Sean J, Haessler, Jeffrey, Bihlmeyer, Nathan A, Grarup, Niels, Lin, Honghuang, Teumer, Alexander, Li-Gao, Ruifang, Yao, Jie, Guo, Xiuqing, Brody, Jennifer A, Müller-Nurasyid, Martina, Schramm, Katharina, Verweij, Niek, van den Berg, Marten E, van Setten, Jessica, Isaacs, Aaron, Ramírez, Julia, Warren, Helen R, Padmanabhan, Sandosh, Kors, Jan A, de Boer, Rudolf A, van der Meer, Peter, Sinner, Moritz F, Waldenberger, Melanie, Psaty, Bruce M, Taylor, Kent D, Völker, Uwe, Kanters, Jørgen K, Li, Man, Alonso, Alvaro, Perez, Marco V, Vaartjes, Ilonca, Bots, Michiel L, Huang, Paul L, Heckbert, Susan R, Lin, Henry J, Kornej, Jelena, Munroe, Patricia B, van Duijn, Cornelia M, Asselbergs, Folkert W, Stricker, Bruno H, van der Harst, Pim, Kääb, Stefan, Peters, Annette, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Dörr, Marcus, Felix, Stephan B, Linneberg, Allan, Hansen, Torben, Arking, Dan E, Kooperberg, Charles, Benjamin, Emelia J, Lunetta, Kathryn L, Ellinor, Patrick T, and Lubitz, Steven A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Research, Genetics, Heart Disease, Cardiovascular, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Atrial Fibrillation, Cardiac Myosins, Connectin, Electrocardiography, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins, Humans, Myosin Heavy Chains, NAV1.8 Voltage-Gated Sodium Channel, Quantitative Trait Loci, Transcription Factors, atrial fibrillation, electrophysiology, exome, genetic, genome-wide association studies, population, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundThe P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.MethodsFifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.ResultsWe identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk.ConclusionsOur results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Published
2020

43. 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 HH, 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, Mosley, Thomas H, Saba, Yasaman, Pirpamer, Lukas, Seiler, Stephan, Becker, James T, Carmichael, Owen, Rotter, Jerome I, Psaty, Bruce M, Lopez, Oscar L, Amin, Najaf, van der Lee, Sven J, Yang, Qiong, Himali, Jayandra J, Maillard, Pauline, Beiser, Alexa S, DeCarli, Charles, Karama, Sherif, Lewis, Lindsay, Harris, Mat, Bastin, Mark E, Deary, Ian J, Veronica Witte, A, Beyer, Frauke, Loeffler, Markus, Mather, Karen A, Schofield, Peter R, Thalamuthu, Anbupalam, Kwok, John B, Wright, Margaret J, Ames, David, Trollor, Julian, Jiang, Jiyang, Brodaty, Henry, Wen, Wei, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G, Niessen, Wiro J, Wittfeld, Katharina, Bülow, Robin, Völker, Uwe, Pausova, Zdenka, Bruce Pike, G, Maingault, Sophie, Crivello, Fabrice, Tzourio, Christophe, Amouyel, Philippe, Mazoyer, Bernard, Neale, Michael C, Franz, Carol E, Lyons, Michael J, Panizzon, Matthew S, Andreassen, Ole A, Dale, Anders M, Logue, Mark, Grasby, Katrina L, Jahanshad, Neda, Painter, Jodie N, Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P, Lind, Penelope A, Pizzagalli, Fabrizio, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, ENIGMA consortium, Sachdev, Perminder S, Kremen, William S, Wardlaw, Joanna M, Villringer, Arno, van Duijn, Cornelia M, Grabe, Hans J, Longstreth, William T, Fornage, Myriam, Paus, Tomas, Debette, Stephanie, Ikram, M Arfan, Schmidt, Helena, Schmidt, Reinhold, and Seshadri, Sudha

Subjects
ENIGMA consortium, Brain, Chromosome Structures, Humans, Neurodegenerative Diseases, Cognition, Mental Disorders, Genomics, Aging, Phenotype, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Genetics, Neurosciences, Human Genome, Brain Disorders, Biotechnology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological
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.

Published
2020

44. ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

Author

Thompson, Paul M, Jahanshad, Neda, Ching, Christopher RK, Salminen, Lauren E, Thomopoulos, Sophia I, Bright, Joanna, Baune, Bernhard T, Bertolín, Sara, Bralten, Janita, Bruin, Willem B, Bülow, Robin, Chen, Jian, Chye, Yann, Dannlowski, Udo, de Kovel, Carolien GF, Donohoe, Gary, Eyler, Lisa T, Faraone, Stephen V, Favre, Pauline, Filippi, Courtney A, Frodl, Thomas, Garijo, Daniel, Gil, Yolanda, Grabe, Hans J, Grasby, Katrina L, Hajek, Tomas, Han, Laura KM, Hatton, Sean N, Hilbert, Kevin, Ho, Tiffany C, Holleran, Laurena, Homuth, Georg, Hosten, Norbert, Houenou, Josselin, Ivanov, Iliyan, Jia, Tianye, Kelly, Sinead, Klein, Marieke, Kwon, Jun Soo, Laansma, Max A, Leerssen, Jeanne, Lueken, Ulrike, Nunes, Abraham, Neill, Joseph O', Opel, Nils, Piras, Fabrizio, Piras, Federica, Postema, Merel C, Pozzi, Elena, Shatokhina, Natalia, Soriano-Mas, Carles, Spalletta, Gianfranco, Sun, Daqiang, Teumer, Alexander, Tilot, Amanda K, Tozzi, Leonardo, van der Merwe, Celia, Van Someren, Eus JW, van Wingen, Guido A, Völzke, Henry, Walton, Esther, Wang, Lei, Winkler, Anderson M, Wittfeld, Katharina, Wright, Margaret J, Yun, Je-Yeon, Zhang, Guohao, Zhang-James, Yanli, Adhikari, Bhim M, Agartz, Ingrid, Aghajani, Moji, Aleman, André, Althoff, Robert R, Altmann, Andre, Andreassen, Ole A, Baron, David A, Bartnik-Olson, Brenda L, Marie Bas-Hoogendam, Janna, Baskin-Sommers, Arielle R, Bearden, Carrie E, Berner, Laura A, Boedhoe, Premika SW, Brouwer, Rachel M, Buitelaar, Jan K, Caeyenberghs, Karen, Cecil, Charlotte AM, Cohen, Ronald A, Cole, James H, Conrod, Patricia J, De Brito, Stephane A, de Zwarte, Sonja MC, Dennis, Emily L, Desrivieres, Sylvane, Dima, Danai, Ehrlich, Stefan, Esopenko, Carrie, Fairchild, Graeme, Fisher, Simon E, Fouche, Jean-Paul, and Francks, Clyde

Subjects
ENIGMA Consortium, Brain, Humans, Magnetic Resonance Imaging, Reproducibility of Results, Depressive Disorder, Major, Neuroimaging, Neurosciences, Clinical Research, Mental Health, Brain Disorders, Behavioral and Social Science, Genetics, Basic Behavioral and Social Science, Prevention, 2.1 Biological and endogenous factors, 2.3 Psychological, social and economic factors, Mental health, Neurological, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Published
2020

45. Full exploitation of high dimensionality in brain imaging: The JPND working group statement and findings

Author

Adams, Hieab HH, Roshchupkin, Gennady V, DeCarli, Charles, Franke, Barbara, Grabe, Hans J, Habes, Mohamad, Jahanshad, Neda, Medland, Sarah E, Niessen, Wiro, Satizabal, Claudia L, Schmidt, Reinhold, Seshadri, Sudha, Teumer, Alexander, Thompson, Paul M, Vernooij, Meike W, Wittfeld, Katharina, and Ikram, M Arfan

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Rare Diseases, Neurodegenerative, Bioengineering, Brain Disorders, Neurological, Generic health relevance, Good Health and Well Being, Neuroimaging, High-dimensional, Voxels, Omics, Genetics, Voxel-based morphometry, Biological psychology
Abstract

Advances in technology enable increasing amounts of data collection from individuals for biomedical research. Such technologies, for example, in genetics and medical imaging, have also led to important scientific discoveries about health and disease. The combination of multiple types of high-throughput data for complex analyses, however, has been limited by analytical and logistic resources to handle high-dimensional data sets. In our previous EU Joint Programme-Neurodegenerative Disease Research (JPND) Working Group, called HD-READY, we developed methods that allowed successful combination of omics data with neuroimaging. Still, several issues remained to fully leverage high-dimensional multimodality data. For instance, high-dimensional features, such as voxels and vertices, which are common in neuroimaging, remain difficult to harmonize. In this Full-HD Working Group, we focused on such harmonization of high-dimensional neuroimaging phenotypes in combination with other omics data and how to make the resulting ultra-high-dimensional data easily accessible in neurodegeneration research.

Published
2019

46. DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood

Author

Hahn, Julie, Bressler, Jan, Domingo-Relloso, Arce, Chen, Ming-Huei, McCartney, Daniel L., Teumer, Alexander, van Dongen, Jenny, Kleber, Marcus E., Aïssi, Dylan, Swenson, Brenton R., Yao, Jie, Zhao, Wei, Huang, Jian, Xia, Yujing, Brown, Michael R., Costeira, Ricardo, de Geus, Eco J.C., Delgado, Graciela E., Dobson, Dre'Von A., Elliott, Paul, Grabe, Hans J., Guo, Xiuqing, Harris, Sarah E., Huffman, Jennifer E., Kardia, Sharon L.R., Liu, Yongmei, Lorkowski, Stefan, Marioni, Riccardo E., Nauck, Matthias, Ratliff, Scott M., Sabater-Lleal, Maria, Spector, Tim D., Suchon, Pierre, Taylor, Kent D., Thibord, Florian, Trégouët, David-Alexandre, Wiggins, Kerri L., Willemsen, Gonneke, Bell, Jordana T., Boomsma, Dorret I., Cole, Shelley A., Cox, Simon R., Dehghan, Abbas, Greinacher, Andreas, Haack, Karin, März, Winfried, Morange, Pierre-Emmanuel, Rotter, Jerome I., Sotoodehnia, Nona, Tellez-Plaza, Maria, Navas-Acien, Ana, Smith, Jennifer A., Johnson, Andrew D., Fornage, Myriam, Smith, Nicholas L., Wolberg, Alisa S., Morrison, Alanna C., and de Vries, Paul S.

Published
2023
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47. A saturated map of common genetic variants associated with human height

Author

Yengo, Loïc, Vedantam, Sailaja, Marouli, Eirini, Sidorenko, Julia, Bartell, Eric, Sakaue, Saori, Graff, Marielisa, Eliasen, Anders U., Jiang, Yunxuan, Raghavan, Sridharan, Miao, Jenkai, Arias, Joshua D., Graham, Sarah E., Mukamel, Ronen E., Spracklen, Cassandra N., Yin, Xianyong, Chen, Shyh-Huei, Ferreira, Teresa, Highland, Heather H., Ji, Yingjie, Karaderi, Tugce, Lin, Kuang, Lüll, Kreete, Malden, Deborah E., Medina-Gomez, Carolina, Machado, Moara, Moore, Amy, Rüeger, Sina, Sim, Xueling, Vrieze, Scott, Ahluwalia, Tarunveer S., Akiyama, Masato, Allison, Matthew A., Alvarez, Marcus, Andersen, Mette K., Ani, Alireza, Appadurai, Vivek, Arbeeva, Liubov, Bhaskar, Seema, Bielak, Lawrence F., Bollepalli, Sailalitha, Bonnycastle, Lori L., Bork-Jensen, Jette, Bradfield, Jonathan P., Bradford, Yuki, Braund, Peter S., Brody, Jennifer A., Burgdorf, Kristoffer S., Cade, Brian E., Cai, Hui, Cai, Qiuyin, Campbell, Archie, Cañadas-Garre, Marisa, Catamo, Eulalia, Chai, Jin-Fang, Chai, Xiaoran, Chang, Li-Ching, Chang, Yi-Cheng, Chen, Chien-Hsiun, Chesi, Alessandra, Choi, Seung Hoan, Chung, Ren-Hua, Cocca, Massimiliano, Concas, Maria Pina, Couture, Christian, Cuellar-Partida, Gabriel, Danning, Rebecca, Daw, E. Warwick, Degenhard, Frauke, Delgado, Graciela E., Delitala, Alessandro, Demirkan, Ayse, Deng, Xuan, Devineni, Poornima, Dietl, Alexander, Dimitriou, Maria, Dimitrov, Latchezar, Dorajoo, Rajkumar, Ekici, Arif B., Engmann, Jorgen E., Fairhurst-Hunter, Zammy, Farmaki, Aliki-Eleni, Faul, Jessica D., Fernandez-Lopez, Juan-Carlos, Forer, Lukas, Francescatto, Margherita, Freitag-Wolf, Sandra, Fuchsberger, Christian, Galesloot, Tessel E., Gao, Yan, Gao, Zishan, Geller, Frank, Giannakopoulou, Olga, Giulianini, Franco, Gjesing, Anette P., Goel, Anuj, Gordon, Scott D., Gorski, Mathias, Grove, Jakob, Guo, Xiuqing, Gustafsson, Stefan, Haessler, Jeffrey, Hansen, Thomas F., Havulinna, Aki S., Haworth, Simon J., He, Jing, Heard-Costa, Nancy, Hebbar, Prashantha, Hindy, George, Ho, Yuk-Lam A., Hofer, Edith, Holliday, Elizabeth, Horn, Katrin, Hornsby, Whitney E., Hottenga, Jouke-Jan, Huang, Hongyan, Huang, Jie, Huerta-Chagoya, Alicia, Huffman, Jennifer E., Hung, Yi-Jen, Huo, Shaofeng, Hwang, Mi Yeong, Iha, Hiroyuki, Ikeda, Daisuke D., Isono, Masato, Jackson, Anne U., Jäger, Susanne, Jansen, Iris E., Johansson, Ingegerd, Jonas, Jost B., Jonsson, Anna, Jørgensen, Torben, Kalafati, Ioanna-Panagiota, Kanai, Masahiro, Kanoni, Stavroula, Kårhus, Line L., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kawaguchi, Takahisa, Kember, Rachel L., Kentistou, Katherine A., Kim, Han-Na, Kim, Young Jin, Kleber, Marcus E., Knol, Maria J., Kurbasic, Azra, Lauzon, Marie, Le, Phuong, Lea, Rodney, Lee, Jong-Young, Leonard, Hampton L., Li, Shengchao A., Li, Xiaohui, Li, Xiaoyin, Liang, Jingjing, Lin, Honghuang, Lin, Shih-Yi, Liu, Jun, Liu, Xueping, Lo, Ken Sin, Long, Jirong, Lores-Motta, Laura, Luan, Jian’an, Lyssenko, Valeriya, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamakou, Vasiliki, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Mattheisen, Manuel, Mavarani, Laven, McDaid, Aaron F., Meidtner, Karina, Melendez, Tori L., Mercader, Josep M., Milaneschi, Yuri, Miller, Jason E., Millwood, Iona Y., Mishra, Pashupati P., Mitchell, Ruth E., Møllehave, Line T., Morgan, Anna, Mucha, Soeren, Munz, Matthias, Nakatochi, Masahiro, Nelson, Christopher P., Nethander, Maria, Nho, Chu Won, Nielsen, Aneta A., Nolte, Ilja M., Nongmaithem, Suraj S., Noordam, Raymond, Ntalla, Ioanna, Nutile, Teresa, Pandit, Anita, Christofidou, Paraskevi, Pärna, Katri, Pauper, Marc, Petersen, Eva R. B., Petersen, Liselotte V., Pitkänen, Niina, Polašek, Ozren, Poveda, Alaitz, Preuss, Michael H., Pyarajan, Saiju, Raffield, Laura M., Rakugi, Hiromi, Ramirez, Julia, Rasheed, Asif, Raven, Dennis, Rayner, Nigel W., Riveros, Carlos, Rohde, Rebecca, Ruggiero, Daniela, Ruotsalainen, Sanni E., Ryan, Kathleen A., Sabater-Lleal, Maria, Saxena, Richa, Scholz, Markus, Sendamarai, Anoop, Shen, Botong, Shi, Jingchunzi, Shin, Jae Hun, Sidore, Carlo, Sitlani, Colleen M., Slieker, Roderick C., Smit, Roelof A. J., Smith, Albert V., Smith, Jennifer A., Smyth, Laura J., Southam, Lorraine, Steinthorsdottir, Valgerdur, Sun, Liang, Takeuchi, Fumihiko, Tallapragada, Divya Sri Priyanka, Taylor, Kent D., Tayo, Bamidele O., Tcheandjieu, Catherine, Terzikhan, Natalie, Tesolin, Paola, Teumer, Alexander, Theusch, Elizabeth, Thompson, Deborah J., Thorleifsson, Gudmar, Timmers, Paul R. H. J., Trompet, Stella, Turman, Constance, Vaccargiu, Simona, van der Laan, Sander W., van der Most, Peter J., van Klinken, Jan B., van Setten, Jessica, Verma, Shefali S., Verweij, Niek, Veturi, Yogasudha, Wang, Carol A., Wang, Chaolong, Wang, Lihua, Wang, Zhe, Warren, Helen R., Bin Wei, Wen, Wickremasinghe, Ananda R., Wielscher, Matthias, Wiggins, Kerri L., Winsvold, Bendik S., Wong, Andrew, Wu, Yang, Wuttke, Matthias, Xia, Rui, Xie, Tian, Yamamoto, Ken, Yang, Jingyun, Yao, Jie, Young, Hannah, Yousri, Noha A., Yu, Lei, Zeng, Lingyao, Zhang, Weihua, Zhang, Xinyuan, Zhao, Jing-Hua, Zhao, Wei, Zhou, Wei, Zimmermann, Martina E., Zoledziewska, Magdalena, Adair, Linda S., Adams, Hieab H. H., Aguilar-Salinas, Carlos A., Al-Mulla, Fahd, Arnett, Donna K., Asselbergs, Folkert W., Åsvold, Bjørn Olav, Attia, John, Banas, Bernhard, Bandinelli, Stefania, Bennett, David A., Bergler, Tobias, Bharadwaj, Dwaipayan, Biino, Ginevra, Bisgaard, Hans, Boerwinkle, Eric, Böger, Carsten A., Bønnelykke, Klaus, Boomsma, Dorret I., Børglum, Anders D., Borja, Judith B., Bouchard, Claude, Bowden, Donald W., Brandslund, Ivan, Brumpton, Ben, Buring, Julie E., Caulfield, Mark J., Chambers, John C., Chandak, Giriraj R., Chanock, Stephen J., Chaturvedi, Nish, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Ching-Yu, Christophersen, Ingrid E., Ciullo, Marina, Cole, John W., Collins, Francis S., Cooper, Richard S., Cruz, Miguel, Cucca, Francesco, Cupples, L. Adrienne, Cutler, Michael J., Damrauer, Scott M., Dantoft, Thomas M., de Borst, Gert J., de Groot, Lisette C. P. G. M., De Jager, Philip L., de Kleijn, Dominique P. V., Janaka de Silva, H., Dedoussis, George V., den Hollander, Anneke I., Du, Shufa, Easton, Douglas F., Elders, Petra J. M., Eliassen, A. Heather, Ellinor, Patrick T., Elmståhl, Sölve, Erdmann, Jeanette, Evans, Michele K., Fatkin, Diane, Feenstra, Bjarke, Feitosa, Mary F., Ferrucci, Luigi, Ford, Ian, Fornage, Myriam, Franke, Andre, Franks, Paul W., Freedman, Barry I., Gasparini, Paolo, Gieger, Christian, Girotto, Giorgia, Goddard, Michael E., Golightly, Yvonne M., Gonzalez-Villalpando, Clicerio, Gordon-Larsen, Penny, Grallert, Harald, Grant, Struan F. A., Grarup, Niels, Griffiths, Lyn, Gudnason, Vilmundur, Haiman, Christopher, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayward, Caroline, Heckbert, Susan R., Heng, Chew-Kiat, Hengstenberg, Christian, Hewitt, Alex W., Hishigaki, Haretsugu, Hoyng, Carel B., Huang, Paul L., Huang, Wei, Hunt, Steven C., Hveem, Kristian, Hyppönen, Elina, Iacono, William G., Ichihara, Sahoko, Ikram, M. Arfan, Isasi, Carmen R., Jackson, Rebecca D., Jarvelin, Marjo-Riitta, Jin, Zi-Bing, Jöckel, Karl-Heinz, Joshi, Peter K., Jousilahti, Pekka, Jukema, J. Wouter, Kähönen, Mika, Kamatani, Yoichiro, Kang, Kui Dong, Kaprio, Jaakko, Kardia, Sharon L. R., Karpe, Fredrik, Kato, Norihiro, Kee, Frank, Kessler, Thorsten, Khera, Amit V., Khor, Chiea Chuen, Kiemeney, Lambertus A. L. M., Kim, Bong-Jo, Kim, Eung Kweon, Kim, Hyung-Lae, Kirchhof, Paulus, Kivimaki, Mika, Koh, Woon-Puay, Koistinen, Heikki A., Kolovou, Genovefa D., Kooner, Jaspal S., Kooperberg, Charles, Köttgen, Anna, Kovacs, Peter, Kraaijeveld, Adriaan, Kraft, Peter, Krauss, Ronald M., Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lange, Leslie A., Langenberg, Claudia, Launer, Lenore J., Le Marchand, Loic, Lee, Hyejin, Lee, Nanette R., Lehtimäki, Terho, Li, Huaixing, Li, Liming, Lieb, Wolfgang, Lin, Xu, Lind, Lars, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Loeffler, Markus, London, Barry, Lubitz, Steven A., Lye, Stephen J., Mackey, David A., Mägi, Reedik, Magnusson, Patrik K. E., Marcus, Gregory M., Vidal, Pedro Marques, Martin, Nicholas G., März, Winfried, Matsuda, Fumihiko, McGarrah, Robert W., McGue, Matt, McKnight, Amy Jayne, Medland, Sarah E., Mellström, Dan, Metspalu, Andres, Mitchell, Braxton D., Mitchell, Paul, Mook-Kanamori, Dennis O., Morris, Andrew D., Mucci, Lorelei A., Munroe, Patricia B., Nalls, Mike A., Nazarian, Saman, Nelson, Amanda E., Neville, Matt J., Newton-Cheh, Christopher, Nielsen, Christopher S., Nöthen, Markus M., Ohlsson, Claes, Oldehinkel, Albertine J., Orozco, Lorena, Pahkala, Katja, Pajukanta, Päivi, Palmer, Colin N. A., Parra, Esteban J., Pattaro, Cristian, Pedersen, Oluf, Pennell, Craig E., Penninx, Brenda W. J. H., Perusse, Louis, Peters, Annette, Peyser, Patricia A., Porteous, David J., Posthuma, Danielle, Power, Chris, Pramstaller, Peter P., Province, Michael A., Qi, Qibin, Qu, Jia, Rader, Daniel J., Raitakari, Olli T., Ralhan, Sarju, Rallidis, Loukianos S., Rao, Dabeeru C., Redline, Susan, Reilly, Dermot F., Reiner, Alexander P., Rhee, Sang Youl, Ridker, Paul M., Rienstra, Michiel, Ripatti, Samuli, Ritchie, Marylyn D., Roden, Dan M., Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Rutters, Femke, Sabanayagam, Charumathi, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sanghera, Dharambir K., Sattar, Naveed, Schmidt, Börge, Schmidt, Helena, Schmidt, Reinhold, Schulze, Matthias B., Schunkert, Heribert, Scott, Laura J., Scott, Rodney J., Sever, Peter, Shiroma, Eric J., Shoemaker, M. Benjamin, Shu, Xiao-Ou, Simonsick, Eleanor M., Sims, Mario, Singh, Jai Rup, Singleton, Andrew B., Sinner, Moritz F., Smith, J. Gustav, Snieder, Harold, Spector, Tim D., Stampfer, Meir J., Stark, Klaus J., Strachan, David P., ‘t Hart, Leen M., Tabara, Yasuharu, Tang, Hua, Tardif, Jean-Claude, Thanaraj, Thangavel A., Timpson, Nicholas J., Tönjes, Anke, Tremblay, Angelo, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tusié-Luna, Maria-Teresa, Uitterlinden, Andre G., van Dam, Rob M., van der Harst, Pim, Van der Velde, Nathalie, van Duijn, Cornelia M., van Schoor, Natasja M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wacher-Rodarte, Niels H., Walker, Mark, Wang, Ya Xing, Wareham, Nicholas J., Watanabe, Richard M., Watkins, Hugh, Weir, David R., Werge, Thomas M., Widen, Elisabeth, Wilkens, Lynne R., Willemsen, Gonneke, Willett, Walter C., Wilson, James F., Wong, Tien-Yin, Woo, Jeong-Taek, Wright, Alan F., Wu, Jer-Yuarn, Xu, Huichun, Yajnik, Chittaranjan S., Yokota, Mitsuhiro, Yuan, Jian-Min, Zeggini, Eleftheria, Zemel, Babette S., Zheng, Wei, Zhu, Xiaofeng, Zmuda, Joseph M., Zonderman, Alan B., Zwart, John-Anker, Chasman, Daniel I., Cho, Yoon Shin, Heid, Iris M., McCarthy, Mark I., Ng, Maggie C. Y., O’Donnell, Christopher J., Rivadeneira, Fernando, Thorsteinsdottir, Unnur, Sun, Yan V., Tai, E. Shyong, Boehnke, Michael, Deloukas, Panos, Justice, Anne E., Lindgren, Cecilia M., Loos, Ruth J. F., Mohlke, Karen L., North, Kari E., Stefansson, Kari, Walters, Robin G., Winkler, Thomas W., Young, Kristin L., Loh, Po-Ru, Yang, Jian, Esko, Tõnu, Assimes, Themistocles L., Auton, Adam, Abecasis, Goncalo R., Willer, Cristen J., Locke, Adam E., Berndt, Sonja I., Lettre, Guillaume, Frayling, Timothy M., Okada, Yukinori, Wood, Andrew R., Visscher, Peter M., and Hirschhorn, Joel N.

Published
2022
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48. Genetic architecture of subcortical brain structures in 38,851 individuals

Author

Satizabal, Claudia L, Adams, Hieab HH, Hibar, Derrek P, White, Charles C, Knol, Maria J, Stein, Jason L, Scholz, Markus, Sargurupremraj, Muralidharan, Jahanshad, Neda, Roshchupkin, Gennady V, Smith, Albert V, Bis, Joshua C, Jian, Xueqiu, Luciano, Michelle, Hofer, Edith, Teumer, Alexander, van der Lee, Sven J, Yang, Jingyun, Yanek, Lisa R, Lee, Tom V, Li, Shuo, Hu, Yanhui, Koh, Jia Yu, Eicher, John D, Desrivières, Sylvane, Arias-Vasquez, Alejandro, Chauhan, Ganesh, Athanasiu, Lavinia, Rentería, Miguel E, Kim, Sungeun, Hoehn, David, Armstrong, Nicola J, Chen, Qiang, Holmes, Avram J, den Braber, Anouk, Kloszewska, Iwona, Andersson, Micael, Espeseth, Thomas, Grimm, Oliver, Abramovic, Lucija, Alhusaini, Saud, Milaneschi, Yuri, Papmeyer, Martina, Axelsson, Tomas, Ehrlich, Stefan, Roiz-Santiañez, Roberto, Kraemer, Bernd, Håberg, Asta K, Jones, Hannah J, Pike, G Bruce, Stein, Dan J, Stevens, Allison, Bralten, Janita, Vernooij, Meike W, Harris, Tamara B, Filippi, Irina, Witte, A Veronica, Guadalupe, Tulio, Wittfeld, Katharina, Mosley, Thomas H, Becker, James T, Doan, Nhat Trung, Hagenaars, Saskia P, Saba, Yasaman, Cuellar-Partida, Gabriel, Amin, Najaf, Hilal, Saima, Nho, Kwangsik, Mirza-Schreiber, Nazanin, Arfanakis, Konstantinos, Becker, Diane M, Ames, David, Goldman, Aaron L, Lee, Phil H, Boomsma, Dorret I, Lovestone, Simon, Giddaluru, Sudheer, Le Hellard, Stephanie, Mattheisen, Manuel, Bohlken, Marc M, Kasperaviciute, Dalia, Schmaal, Lianne, Lawrie, Stephen M, Agartz, Ingrid, Walton, Esther, Tordesillas-Gutierrez, Diana, Davies, Gareth E, Shin, Jean, Ipser, Jonathan C, Vinke, Louis N, Hoogman, Martine, Jia, Tianye, Burkhardt, Ralph, Klein, Marieke, Crivello, Fabrice, Janowitz, Deborah, Carmichael, Owen, Haukvik, Unn K, Aribisala, Benjamin S, and Schmidt, Helena

Subjects
Biological Sciences, Genetics, Brain Disorders, Mental Health, Neurosciences, Human Genome, 2.1 Biological and endogenous factors, Neurological, Adult, Aged, Animals, Brain, Cohort Studies, Drosophila melanogaster, Genetic Variation, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders, Organ Size, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019

49. 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, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O, van der Most, Peter J, Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan JL, Baptista, Daniela, Biggs, Mary L, Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J, Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P, Coresh, Josef, Corre, Tanguy, Danesh, John, de Borst, Martin H, De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko PJ, Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F, Franco, Oscar H, Franke, Andre, Freedman, Barry I, Freitag-Wolf, Sandra, Gansevoort, Ron T, Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B, Hicks, Andrew A, Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M Arfan, Ingelsson, Erik, Jaddoe, Vincent WV, Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K, Kronenberg, Florian, Lange, Leslie A, Langefeld, Carl D, Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M, Liu, Jianjun, and Loeffler, Markus

Subjects
Animals, Humans, Drosophila melanogaster, Albuminuria, Diabetes Mellitus, Genetic Predisposition to Disease, Creatinine, Risk Factors, Chromosome Mapping, Gene Expression Regulation, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Phenomics
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.

Published
2019

50. New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

Author

Evangelou, Evangelos, Gao, He, Chu, Congying, Ntritsos, Georgios, Blakeley, Paul, Butts, Andrew R, Pazoki, Raha, Suzuki, Hideaki, Koskeridis, Fotios, Yiorkas, Andrianos M, Karaman, Ibrahim, Elliott, Joshua, Luo, Qiang, Aeschbacher, Stefanie, Bartz, Traci M, Baumeister, Sebastian E, Braund, Peter S, Brown, Michael R, Brody, Jennifer A, Clarke, Toni-Kim, Dimou, Niki, Faul, Jessica D, Homuth, Georg, Jackson, Anne U, Kentistou, Katherine A, Joshi, Peter K, Lemaitre, Rozenn N, Lind, Penelope A, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Milaneschi, Yuri, Nelson, Christopher P, Nolte, Ilja M, Perälä, Mia-Maria, Polasek, Ozren, Porteous, David, Ratliff, Scott M, Smith, Jennifer A, Stančáková, Alena, Teumer, Alexander, Tuominen, Samuli, Thériault, Sébastien, Vangipurapu, Jagadish, Whitfield, John B, Wood, Alexis, Yao, Jie, Yu, Bing, Zhao, Wei, Arking, Dan E, Auvinen, Juha, Liu, Chunyu, Männikkö, Minna, Risch, Lorenz, Rotter, Jerome I, Snieder, Harold, Veijola, Juha, Blakemore, Alexandra I, Boehnke, Michael, Campbell, Harry, Conen, David, Eriksson, Johan G, Grabe, Hans J, Guo, Xiuqing, van der Harst, Pim, Hartman, Catharina A, Hayward, Caroline, Heath, Andrew C, Jarvelin, Marjo-Riitta, Kähönen, Mika, Kardia, Sharon LR, Kühne, Michael, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Lehtimäki, Terho, McIntosh, Andrew M, Mohlke, Karen L, Morrison, Alanna C, Martin, Nicholas G, Oldehinkel, Albertine J, Penninx, Brenda WJH, Psaty, Bruce M, Raitakari, Olli T, Rudan, Igor, Samani, Nilesh J, Scott, Laura J, Spector, Tim D, Verweij, Niek, Weir, David R, Wilson, James F, Levy, Daniel, Tzoulaki, Ioanna, Bell, Jimmy D, Matthews, Paul M, Rothenfluh, Adrian, Desrivières, Sylvane, Schumann, Gunter, and Elliott, Paul

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Epidemiology, Health Sciences, Psychology, Pharmacology and Pharmaceutical Sciences, Biotechnology, Substance Misuse, Brain Disorders, Mental Health, Neurosciences, Serious Mental Illness, Alcoholism, Alcohol Use and Health, Schizophrenia, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Mental health, Stroke, Cancer, Oral and gastrointestinal, Good Health and Well Being, Adult, Aged, Alcohol Drinking, Alcoholism, Brain, Female, Genes, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Mental Disorders, Middle Aged, Neuroimaging, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Biomedical and clinical sciences, Health sciences
Abstract

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

Published
2019

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