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1. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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2. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes

Author

Parsa Akbari, Olukayode A. Sosina, Jonas Bovijn, Karl Landheer, Jonas B. Nielsen, Minhee Kim, Senem Aykul, Tanima De, Mary E. Haas, George Hindy, Nan Lin, Ian R. Dinsmore, Jonathan Z. Luo, Stefanie Hectors, Benjamin Geraghty, Mary Germino, Lampros Panagis, Prodromos Parasoglou, Johnathon R. Walls, Gabor Halasz, Gurinder S. Atwal, Regeneron Genetics Center, DiscovEHR Collaboration, Marcus Jones, Michelle G. LeBlanc, Christopher D. Still, David J. Carey, Alice Giontella, Marju Orho-Melander, Jaime Berumen, Pablo Kuri-Morales, Jesus Alegre-Díaz, Jason M. Torres, Jonathan R. Emberson, Rory Collins, Daniel J. Rader, Brian Zambrowicz, Andrew J. Murphy, Suganthi Balasubramanian, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Michael Cantor, Goncalo R. Abecasis, Manuel A. R. Ferreira, Mark W. Sleeman, Viktoria Gusarova, Judith Altarejos, Charles Harris, Aris N. Economides, Vincent Idone, Katia Karalis, Giusy Della Gatta, Tooraj Mirshahi, George D. Yancopoulos, Olle Melander, Jonathan Marchini, Roberto Tapia-Conyer, Adam E. Locke, Aris Baras, Niek Verweij, and Luca A. Lotta

Subjects
Science
Abstract

Fat distribution is associated with cardiometabolic disease, although it has been less well studied than overall obesity. In a multiancestry exome-sequencing study, the authors identified predicted loss-of-function mutations in INHBE associated with favorable fat distribution and protection from type 2 diabetes.

Published
2022
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3. Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Author

Xianyong Yin, Lap Sum Chan, Debraj Bose, Anne U. Jackson, Peter VandeHaar, Adam E. Locke, Christian Fuchsberger, Heather M. Stringham, Ryan Welch, Ketian Yu, Lilian Fernandes Silva, Susan K. Service, Daiwei Zhang, Emily C. Hector, Erica Young, Liron Ganel, Indraniel Das, Haley Abel, Michael R. Erdos, Lori L. Bonnycastle, Johanna Kuusisto, Nathan O. Stitziel, Ira M. Hall, Gregory R. Wagner, FinnGen, Jian Kang, Jean Morrison, Charles F. Burant, Francis S. Collins, Samuli Ripatti, Aarno Palotie, Nelson B. Freimer, Karen L. Mohlke, Laura J. Scott, Xiaoquan Wen, Eric B. Fauman, Markku Laakso, and Michael Boehnke

Subjects
Science
Abstract

The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms.

Published
2022
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4. Whole Exome Sequencing Enhanced Imputation Identifies 85 Metabolite Associations in the Alpine CHRIS Cohort

Author

Eva König, Johannes Rainer, Vinicius Verri Hernandes, Giuseppe Paglia, Fabiola Del Greco M., Daniele Bottigliengo, Xianyong Yin, Lap Sum Chan, Alexander Teumer, Peter P. Pramstaller, Adam E. Locke, and Christian Fuchsberger

Subjects
GWAS, ExWAS, association study, whole-exome sequencing, imputation, metabolomics, Microbiology, QR1-502
Abstract

Metabolites are intermediates or end products of biochemical processes involved in both health and disease. Here, we take advantage of the well-characterized Cooperative Health Research in South Tyrol (CHRIS) study to perform an exome-wide association study (ExWAS) on absolute concentrations of 175 metabolites in 3294 individuals. To increase power, we imputed the identified variants into an additional 2211 genotyped individuals of CHRIS. In the resulting dataset of 5505 individuals, we identified 85 single-variant genetic associations, of which 39 have not been reported previously. Fifteen associations emerged at ten variants with >5-fold enrichment in CHRIS compared to non-Finnish Europeans reported in the gnomAD database. For example, the CHRIS-enriched ETFDH stop gain variant p.Trp286Ter (rs1235904433-hexanoylcarnitine) and the MCCC2 stop lost variant p.Ter564GlnextTer3 (rs751970792-carnitine) have been found in patients with glutaric acidemia type II and 3-methylcrotonylglycinuria, respectively, but the loci have not been associated with the respective metabolites in a genome-wide association study (GWAS) previously. We further identified three gene-trait associations, where multiple rare variants contribute to the signal. These results not only provide further evidence for previously described associations, but also describe novel genes and mechanisms for diseases and disease-related traits.

Published
2022
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5. Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

Author

Jedidiah Carlson, Adam E. Locke, Matthew Flickinger, Matthew Zawistowski, Shawn Levy, Richard M. Myers, Michael Boehnke, Hyun Min Kang, Laura J. Scott, Jun Z. Li, Sebastian Zöllner, and The BRIDGES Consortium

Subjects
Science
Abstract

Germline mutation rate is a critical parameter in the study of genetics and evolution. Here, Carlson et al. infer fine-scale patterns of human mutation rate heterogeneity by analyzing ~36 million singleton variants from 3560 whole-genome sequences.

Published
2018
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6. Germline Mutations in CIDEB and Protection against Liver Disease

Author

Niek Verweij, Mary E. Haas, Jonas B. Nielsen, Olukayode A. Sosina, Minhee Kim, Parsa Akbari, Tanima De, George Hindy, Jonas Bovijn, Trikaldarshi Persaud, Lawrence Miloscio, Mary Germino, Lampros Panagis, Kyoko Watanabe, Joelle Mbatchou, Marcus Jones, Michelle LeBlanc, Suganthi Balasubramanian, Craig Lammert, Sofia Enhörning, Olle Melander, David J. Carey, Christopher D. Still, Tooraj Mirshahi, Daniel J. Rader, Prodromos Parasoglou, Johnathon R. Walls, John D. Overton, Jeffrey G. Reid, Aris Economides, Michael N. Cantor, Brian Zambrowicz, Andrew J. Murphy, Goncalo R. Abecasis, Manuel A.R. Ferreira, Eriks Smagris, Viktoria Gusarova, Mark Sleeman, George D. Yancopoulos, Jonathan Marchini, Hyun M. Kang, Katia Karalis, Alan R. Shuldiner, Giusy Della Gatta, Adam E. Locke, Aris Baras, and Luca A. Lotta

Subjects
General Medicine
Published
2022

7. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Author

Duncan S. Palmer, Daniel P. Howrigan, Sinéad B. Chapman, Rolf Adolfsson, Nick Bass, Douglas Blackwood, Marco P. M. Boks, Chia-Yen Chen, Claire Churchhouse, Aiden P. Corvin, Nicholas Craddock, David Curtis, Arianna Di Florio, Faith Dickerson, Nelson B. Freimer, Fernando S. Goes, Xiaoming Jia, Ian Jones, Lisa Jones, Lina Jonsson, Rene S. Kahn, Mikael Landén, Adam E. Locke, Andrew M. McIntosh, Andrew McQuillin, Derek W. Morris, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Nancy L. Pedersen, Danielle Posthuma, Andreas Reif, Neil Risch, Catherine Schaefer, Laura Scott, Tarjinder Singh, Jordan W. Smoller, Matthew Solomonson, David St. Clair, Eli A. Stahl, Annabel Vreeker, James T. R. Walters, Weiqing Wang, Nicholas A. Watts, Robert Yolken, Peter P. Zandi, Benjamin M. Neale, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Child and Adolescent Psychiatry / Psychology, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, and Amsterdam Reproduction & Development (AR&D)

Subjects
Bipolar Disorder, Human Genome, A Kinase Anchor Proteins, Biological Sciences, Serious Mental Illness, Medical and Health Sciences, Article, Brain Disorders, Mental Health, SDG 3 - Good Health and Well-being, Clinical Research, Exome Sequencing, Schizophrenia, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Exome, Aetiology, Genome-Wide Association Study, Biotechnology, Developmental Biology
Abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10−9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Published
2022

8. Supplementary Tables S1-3 from Mendelian Randomization Study of Body Mass Index and Colorectal Cancer Risk

Author

Peter T. Campbell, Li Hsu, Emily White, Hermann Brenner, Michael Hoffmeister, Polly A. Newcomb, John D. Potter, Cornelia M. Ulrich, John L. Hopper, Mark A. Jenkins, Aung Ko Win, Michelle Cotterchio, Stephen N. Thibodeau, Kana Wu, Mingyang Song, Daniela Seminara, Noralane M. Lindor, Loïc Le Marchand, David J. Duggan, Mark Thornquist, Tabitha A. Harrison, Mengmeng Du, Robert W. Haile, Graham Casey, Stephen J. Chanock, Sonja I. Berndt, Shuji Ogino, Bette J. Caan, John A. Baron, Richard B. Hayes, Steven Gallinger, Tune H. Pers, Anne E. Justice, Bratati Kahali, Adam E. Locke, Andrew T. Chan, Martha L. Slattery, Anja Rudolph, Jenny Chang-Claude, Ulrike Peters, Jian Gong, and Aaron P. Thrift

Abstract

Supplementary Tables S1-3. Supplementary Table S1 Description of the characteristics by study. Supplementary Table S2 Associations between confounders and body mass index and the weighted genetic risk score among controls. Supplementary Table S3 Odds ratios (OR) and 95% confidence intervals (CI) for the association between a 1-unit increase in the weighted genetic risk score (the instrumental variable [IV]) and risk of colorectal cancer.

Published
2023

9. Data from Mendelian Randomization Study of Body Mass Index and Colorectal Cancer Risk

Author

Peter T. Campbell, Li Hsu, Emily White, Hermann Brenner, Michael Hoffmeister, Polly A. Newcomb, John D. Potter, Cornelia M. Ulrich, John L. Hopper, Mark A. Jenkins, Aung Ko Win, Michelle Cotterchio, Stephen N. Thibodeau, Kana Wu, Mingyang Song, Daniela Seminara, Noralane M. Lindor, Loïc Le Marchand, David J. Duggan, Mark Thornquist, Tabitha A. Harrison, Mengmeng Du, Robert W. Haile, Graham Casey, Stephen J. Chanock, Sonja I. Berndt, Shuji Ogino, Bette J. Caan, John A. Baron, Richard B. Hayes, Steven Gallinger, Tune H. Pers, Anne E. Justice, Bratati Kahali, Adam E. Locke, Andrew T. Chan, Martha L. Slattery, Anja Rudolph, Jenny Chang-Claude, Ulrike Peters, Jian Gong, and Aaron P. Thrift

Abstract

Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer.Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis.Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92).Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation.Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.

Published
2023

10. Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

Author

Xianyong Yin, Debraj Bose, Annie Kwon, Sarah C. Hanks, Anne U. Jackson, Heather M. Stringham, Ryan Welch, Anniina Oravilahti, Lilian Fernandes Silva, Adam E. Locke, Christian Fuchsberger, Susan K. Service, Michael R. Erdos, Lori L. Bonnycastle, Johanna Kuusisto, Nathan O. Stitziel, Ira M. Hall, Jean Morrison, Samuli Ripatti, Aarno Palotie, Nelson B. Freimer, Francis S. Collins, Karen L. Mohlke, Laura J. Scott, Eric B. Fauman, Charles Burant, Michael Boehnke, Markku Laakso, Xiaoquan Wen, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Faculty Common Matters (Faculty of Social Sciences), University of Helsinki, Research Programs Unit, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Clinicum, and Helsinki Institute of Life Science HiLIFE

Subjects
Male, Genome-wide association, Loci, Macular degeneration, Quantitative Trait Loci, 1184 Genetics, developmental biology, physiology, Bilirubin, Colocalization, Glycerophospholipids, Large-scale, Genetic-variants, Carnitine, Complex, Genetics, Mendelian randomization, Prevalence, Humans, Metabolomics, Solute Carrier Family 22 Member 5, Transcriptome, Genetics (clinical), Eqtl, Genome-Wide Association Study
Abstract

Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite levels were more likely to influence gene expression and disease risk compared to the ones that do not. Integrating transcriptomics with metabolomics results prioritized 397 genes for 521 metabolites, including 496 previously identified gene-metabolite pairs with strong functional connections and suggested 33.3% of such gene-metabolite pairs shared the same causal variants with genetic associations of gene expression. Integrating transcriptomics and metabolomics individually with FinnGen GWAS results identified 1,597 genes for 790 disease traits. Integrating transcriptomics and metabolomics jointly with FinnGen GWAS results helped pinpoint metabolic pathways from genes to diseases. We identified putative causal effects of UGT1A1/UGT1A4 expression on gallbladder disorders through regulating plasma (E,E)-bilirubin levels, of SLC22A5 expression on nasal polyps and plasma carnitine levels through distinct pathways, and of LIPC expression on age-related macular degeneration through glycerophospholipid metabolic pathways. Our study highlights the power of integrating multiple sets of molecular traits and GWAS results to deepen understanding of disease pathophysiology.

Published
2022

11. Germline Mutations in

Author

Niek, Verweij, Mary E, Haas, Jonas B, Nielsen, Olukayode A, Sosina, Minhee, Kim, Parsa, Akbari, Tanima, De, George, Hindy, Jonas, Bovijn, Trikaldarshi, Persaud, Lawrence, Miloscio, Mary, Germino, Lampros, Panagis, Kyoko, Watanabe, Joelle, Mbatchou, Marcus, Jones, Michelle, LeBlanc, Suganthi, Balasubramanian, Craig, Lammert, Sofia, Enhörning, Olle, Melander, David J, Carey, Christopher D, Still, Tooraj, Mirshahi, Daniel J, Rader, Prodromos, Parasoglou, Johnathon R, Walls, John D, Overton, Jeffrey G, Reid, Aris, Economides, Michael N, Cantor, Brian, Zambrowicz, Andrew J, Murphy, Goncalo R, Abecasis, Manuel A R, Ferreira, Eriks, Smagris, Viktoria, Gusarova, Mark, Sleeman, George D, Yancopoulos, Jonathan, Marchini, Hyun M, Kang, Katia, Karalis, Alan R, Shuldiner, Giusy, Della Gatta, Adam E, Locke, Aris, Baras, and Luca A, Lotta

Subjects
Liver, Liver Diseases, Exome Sequencing, Humans, Genetic Predisposition to Disease, Apoptosis Regulatory Proteins, Germ-Line Mutation, Transaminases
Abstract

Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants inRare germline mutations in

Published
2022

12. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity

Author

Jack A. Kosmicki, Charles Paulding, Nan Lin, Andrew J. Murphy, Jerome I. Rotter, Brian Zambrowicz, Niek Verweij, Luca A. Lotta, Michal L. Schwartzman, Giusy Della Gatta, Yii-Der Ida Chen, Alexander H. Li, Suganthi Balasubramanian, Jason M. Torres, Hyun Min Kang, Rory Collins, Parsa Akbari, Michael E. Dunn, Gonçalo R. Abecasis, Christian Benner, David J. Carey, Svati H. Shah, Jonathan Marchini, Giovanni Coppola, Marcus B. Jones, Olle Melander, Christopher D. Still, Yi-Ya Fang, Olukayode A. Sosina, Manuel A. R. Ferreira, Roberto Tapia-Conyer, Michael Cantor, Aris N. Economides, Dylan Sun, Adam E. Locke, Jonathan V. Pascale, Daniel J. Rader, Ankit Gilani, Joelle Mbatchou, Jesus Alegre-Díaz, Mark W. Sleeman, Trikaldarshi Persaud, Jeffrey G. Reid, Pablo Kuri-Morales, Jaime Berumen-Campos, John D. Overton, Aris Baras, Ercument Dirice, Sakib Hossain, Alicia Hawes, George D. Yancopoulos, Jonathan Emberson, Victor Garcia, Judith Altarejos, Lori Khrimian, Katia Karalis, William E. Kraus, Tooraj Mirshahi, Kevin Agostinucci, Alan R. Shuldiner, Center, Regeneron Genetics, and Collaboration, DiscovEHR

Subjects
0301 basic medicine, Genetics, medicine.medical_specialty, Multidisciplinary, Body Weight, Genomics, Organ Size, Biology, medicine.disease, Obesity, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Genetic variation, medicine, Medical genetics, Humans, medicine.symptom, Body mass index, Weight gain, 030217 neurology & neurosurgery, Exome sequencing, Glycemic
Abstract

Introduction Obesity accounts for a substantial and growing burden of disease globally. Body adiposity is highly heritable, and human genetic studies can lead to biological and therapeutic insights. Rationale Whole-exome sequencing of hundreds of thousands of individuals is complementary to approaches used to date in obesity genetics and has the potential to identify rare protein-coding variants with large phenotypic impact. We sequenced the exomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with body mass index (BMI), a measure of overall adiposity used to define obesity in clinical practice. We complemented exome sequencing with fine-mapping of common alleles, polygenic score analysis, and in vitro and in vivo modeling work. Results We identified 16 genes for which the burden of rare nonsynonymous variants was associated with BMI at exome-wide statistical significance (inverse-variance weighted meta-analysis P < 3.6 × 10−7), including associations at five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). We observed an overrepresentation of genes highly expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance. Protein-truncating variants in GPR75 were found in ~4/10,000 sequenced people and were associated with 1.8 kg/m2 lower BMI, 5.3 kg lower bodyweight, and 54% lower odds of obesity in heterozygous carriers. Knock out of Gpr75 in mice resulted in resistance to weight gain in a high-fat diet model, which was allele-dose dependent (25% and 44% lower weight gain, respectively, for heterozygous Gpr75−/+ mice and knockout Gpr75−/− mice compared with wild type) and accompanied by improved glycemic control and insulin sensitivity. Protein-truncating variants in CALCR were associated with higher BMI and obesity risk, whereas protein-truncating variants in GIPR and two missense alleles [Arg190→Gln (Arg190Gln), Glu288Gly], which we show result in loss of function in vitro, were associated with lower adiposity. Among monogenic obesity genes in the leptin-melanocortin pathway, heterozygous predicted loss-of-function variants in LEP, POMC, PCSK1, and MC4R (but not LEPR) were associated with higher BMI. Rare protein-truncating variants in UBR2, ANO4, and PCSK1 were associated with more than twofold higher odds of obesity in heterozygous carriers, similar to predicted-deleterious nonsynonymous variants in MC4R, which are considered the most common cause of monogenic obesity. Polygenic predisposition due to >2 million common genetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. Conclusion These results suggest that inhibition of GPR75 may be a therapeutic strategy for obesity and illustrate the power of massive-scale exome sequencing for the identification of large-effect coding variant associations and drug targets for complex traits.

Published
2022

13. Heterozygous variants of CLPB are a cause of severe congenital neutropenia

Author

Christine Bellanné-Chantelot, James Shorter, Julia T. Warren, Vahagn Makaryan, Adam E. Locke, Meredith L Kelley, David C. Dale, Audrey Anna Bolyard, Daniel C. Link, Peeradol Wattanasirakul, Natalie L Kingston, Ryan R. Cupo, Jean Donadieu, and David H. Spencer

Subjects
Male, Models, Molecular, Heterozygote, Neutropenia, Immunology, Biology, Biochemistry, Phagocytes, Granulocytes, and Myelopoiesis, Cataracts, medicine, DiGeorge Syndrome, Congenital Bone Marrow Failure Syndromes, Missense mutation, Humans, Exome, Congenital Neutropenia, Cells, Cultured, Exome sequencing, Genetics, Wild type, Genetic Variation, Infant, Endopeptidase Clp, Cell Biology, Hematology, medicine.disease, Haematopoiesis, Mutation, Female, CLPB
Abstract

Severe congenital neutropenia is an inborn disorder of granulopoiesis. Approximately one third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 severe congenital neutropenia cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPB encodes an adenosine triphosphatase that is implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPB are associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the adenosine triphosphate-binding pocket. Both genetic loss of CLPB and expression of CLPB variants result in impaired granulocytic differentiation of human hematopoietic progenitor cells and increased apoptosis. These CLPB variants associate with wild-type CLPB and inhibit its adenosine triphosphatase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.

Published
2022

14. Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits

Author

Aldons J. Lusis, Karen L. Mohlke, Maren E Cannon, Mete Civelek, Michael Boehnke, Laura J. Scott, Chelsea K. Raulerson, Terrence S. Furey, Heather M. Stringham, Cassandra N. Spracklen, Anne U. Jackson, Francis S. Collins, Arthur Ko, Danyu Lin, Adam E. Locke, Michael I. Love, Päivi Pajukanta, Ying Wu, Christian Fuchsberger, John C. Kidd, Johanna Kuusisto, Markku Laakso, Kevin W Currin, Narisu Narisu, Sarah M Brotman, and Ryan P. Welch

Subjects
Male, Candidate gene, Quantitative Trait Loci, Gene Expression, Adipose tissue, Genome-wide association study, Quantitative trait locus, Biology, Article, Body Mass Index, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Genetics, medicine, Humans, Obesity, Alleles, Finland, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Waist-Hip Ratio, medicine.disease, Adipose Tissue, Diabetes Mellitus, Type 2, chemistry, Expression quantitative trait loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL

Published
2019

15. Genetic and functional evidence links a missense variant in

Author

May E, Montasser, Cristopher V, Van Hout, Lawrence, Miloscio, Alicia D, Howard, Avraham, Rosenberg, Myrasol, Callaway, Biao, Shen, Ning, Li, Adam E, Locke, Niek, Verweij, Tanima, De, Manuel A, Ferreira, Luca A, Lotta, Aris, Baras, Thomas J, Daly, Suzanne A, Hartford, Wei, Lin, Yuan, Mao, Bin, Ye, Derek, White, Guochun, Gong, James A, Perry, Kathleen A, Ryan, Qing, Fang, Gannie, Tzoneva, Evangelos, Pefanis, Charleen, Hunt, Yajun, Tang, Lynn, Lee, Carole, Sztalryd-Woodle, Braxton D, Mitchell, Matthew, Healy, Elizabeth A, Streeten, Simeon I, Taylor, Jeffrey R, O'Connell, Aris N, Economides, Giusy, Della Gatta, and Alan R, Shuldiner

Subjects
Male, Glycosylation, Whole Genome Sequencing, Mutation, Missense, Fibrinogen, Galactose, Cholesterol, LDL, Coronary Artery Disease, Galactosyltransferases, N-Acetylneuraminic Acid, Mice, Liver, Polysaccharides, Gene Knockdown Techniques, Animals, Humans, Female, Gene Knock-In Techniques, Glycoproteins
Abstract

Increased blood levels of low-density lipoprotein cholesterol (LDL-C) and fibrinogen are independent risk factors for cardiovascular disease. We identified associations between an Amish-enriched missense variant (p.Asn352Ser) in a functional domain of beta-1,4-galactosyltransferase 1 (

Published
2021

16. Genome-wide association study of 1,391 plasma metabolites in 6,136 Finnish men identifies 303 novel signals and provides biological insights into human diseases

Author

Peter VandeHaar, Eric B. Fauman, Samuli Ripatti, Nelson B. Freimer, Michael R. Erdos, Debraj Bose, Heather M. Stringham, Xianyong Yin, Nathan O. Stitziel, Ketian Yu, Johanna Kuusisto, Xiaoquan Wen, Anne U. Jackson, Jean Morrison, Aarno Palotie, FinnGen, Lori L. Bonnycastle, Markku Laakso, Christian Fuchsberger, Liron Ganel, Laura J. Scott, Lilian Fernandes Silva, Ira M. Hall, Daiwei Zhang, Erica Young, Gregory R. Wagner, Indraniel Das, Michael Boehnke, Adam E. Locke, Francis S. Collins, Lap Sum Chan, Haley J. Abel, Charles F. Burant, Karen L. Mohlke, Jian Kang, and Emily C. Hector

Subjects
Genetics, Minor allele frequency, Genome-wide association study, Biology
Abstract

Few studies have explored the impact of rare variants (minor allele frequency, MAF

Published
2021

17. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Author

Arianna DiFlorio, Patrick F. Sullivan, Sebastian Zöllner, Margarita Rivera, Richard M. Myers, Stanley J. Watson, Jun Li, Anders Juréus, Sarah E. Bergen, Gonçalo R. Abecasis, Jordan W. Smoller, Michael Conlon O'Donovan, Neil Risch, Hoang T. Nguyen, Chen Jiang, Xiaoming Jia, Mehdi Pirooznia, Danielle Posthuma, Adam E. Locke, Peter P. Zandi, John B. Vincent, Niamh Mullins, Duncan Palmer, Shaun Purcell, Gerome Breen, Christina M. Hultman, Andreas Reif, Khanh K. Thai, Virginia L. Willour, Pui-Yan Kwok, Laura J. Scott, Anne U. Jackson, Michael John Owen, Fernando S. Goes, Steven A. McCarroll, James B. Potash, Mikael Landén, Jennifer L. Moran, Michele T. Pato, Hyun Min Kang, Marco P. Boks, Sinéad B. Chapman, W. Richard McCombie, Janet L. Sobell, Matthew Zawistowski, Rolf Adolfsson, Yongwen Zhuang, Michael Boehnke, René S. Kahn, Huda Akil, James T.R. Walters, Margit Burmeister, Douglas Blackwood, Cathryn M. Lewis, Eli A. Stahl, Mark N. Kvale, Melissa DelaBastide, Catherine Schaefer, Benjamin M. Neale, Giulio Genovese, Carlos N. Pato, Nicholas John Craddock, Andrew McQuillin, Shawn Levy, Aiden Corvin, Pamela Sklar, Weiqing Wang, Andrew M. McIntosh, Ling Shen, Eric T. Monson, Derek W. Morris, Douglas M. Ruderfer, Roel A. Ophoff, Peter McGuffin, Sarah Cohen-Woods, Willem H. Ouwehand, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Goes, Fernando S [0000-0001-6262-8264], Locke, Adam E [0000-0001-6227-198X], Palmer, Duncan [0000-0002-0824-0047], Wang, Weiqing [0000-0003-1565-0148], Genovese, Giulio [0000-0003-3066-5575], Jackson, Anne U [0000-0002-9672-2547], Nguyen, Hoang [0000-0001-6910-7269], Pirooznia, Mehdi [0000-0002-4210-6458], Zawistowski, Matthew [0000-0002-3005-083X], Abecasis, Gonçalo [0000-0003-1509-1825], Bergen, Sarah [0000-0002-5888-0034], Burmeister, Margit [0000-0002-1914-2434], Kwok, Pui-Yan [0000-0002-5087-3059], Li, Jun Z [0000-0001-6727-0812], Levy, Shawn E [0000-0002-1369-5740], Watson, Stanley [0000-0003-4980-5523], Blackwood, Douglas [0000-0002-4076-9346], Boehnke, Michael [0000-0002-6442-7754], Breen, Gerome [0000-0003-2053-1792], Landen, Mikael [0000-0002-4496-6451], Lewis, Cathryn [0000-0002-8249-8476], McCarroll, Steven A [0000-0002-6954-8184], McIntosh, Andrew [0000-0002-0198-4588], McQuillin, Andrew [0000-0003-1567-2240], Morris, Derek [0000-0002-3413-570X], O'Donovan, Michael [0000-0001-7073-2379], Boks, Marco [0000-0001-6163-7484], Kahn, Rene [0000-0001-5909-8004], Ouwehand, Willem [0000-0002-7744-1790], Owen, Michael [0000-0003-4798-0862], Potash, James B [0000-0002-5802-8079], Reif, Andreas [0000-0002-0992-634X], Vincent, John [0000-0003-0692-2519], Neale, Benjamin [0000-0003-1513-6077], Purcell, Shaun [0000-0002-7402-5812], Schaefer, Catherine [0000-0003-2644-055X], Stahl, Eli A [0000-0002-1192-0561], Zandi, Peter P [0000-0001-8423-2623], Scott, Laura J [0000-0002-4886-5084], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Digital Health

Subjects
Bipolar Disorder, Genome-wide association study, Biology, Medical and Health Sciences, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Clinical Research, Genetic variation, medicine, Genetics, 2.1 Biological and endogenous factors, Humans, Exome, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, Molecular Biology, Gene, 030304 developmental biology, Medicinsk genetik, Psychiatry, 0303 health sciences, Prevention, Human Genome, Psychology and Cognitive Sciences, Genetic Variation, Single Nucleotide, Heritability, Biological Sciences, medicine.disease, Serious Mental Illness, Phenotype, 3. Good health, Brain Disorders, Psychiatry and Mental health, Mental Health, Schizophrenia, Medical Genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., International Bipolar Sequencing Consortium (NIMH) R01 MH 110437, Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH) UO1 MH105653, Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH) R01 MH 094145, Multi-ethnic GWAS of Bipolar I Disorder (NIH) R01 MH 085543, Genetic Epidemiology Research in Adult Health and Aging (GERA) RC2 AG036607, Kaiser Permanente Research Program on Genes, Environment, and Health, Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH) R01 MH 087979 MH 087992, 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH095034, 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106531, 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH077139, 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106527, Dalio Foundation

Published
2021

18. Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Author

Xianyong, Yin, Lap Sum, Chan, Debraj, Bose, Anne U, Jackson, Peter, VandeHaar, Adam E, Locke, Christian, Fuchsberger, Heather M, Stringham, Ryan, Welch, Ketian, Yu, Lilian, Fernandes Silva, Susan K, Service, Daiwei, Zhang, Emily C, Hector, Erica, Young, Liron, Ganel, Indraniel, Das, Haley, Abel, Michael R, Erdos, Lori L, Bonnycastle, Johanna, Kuusisto, Nathan O, Stitziel, Ira M, Hall, Gregory R, Wagner, Jian, Kang, Jean, Morrison, Charles F, Burant, Francis S, Collins, Samuli, Ripatti, Aarno, Palotie, Nelson B, Freimer, Karen L, Mohlke, Laura J, Scott, Xiaoquan, Wen, Eric B, Fauman, and Markku, Laakso

Subjects
Male, Phenotype, Gene Frequency, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Alleles, Finland, Genome-Wide Association Study
Abstract

Few studies have explored the impact of rare variants (minor allele frequency 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.

Published
2021

19. Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences

Author

Charleston W. K. Chiang, Ira M. Hall, Nelson B. Freimer, Aarno Palotie, Michael Boehnke, David E. Larson, Alexandra J. Scott, Krishna L. Kanchi, Allison A. Regier, Lei Chen, Erica Young, Johanna Kuusisto, Samuli Ripatti, Chul Joo Kang, Nathan O. Stitziel, Ryan Christ, Haley J. Abel, Indraniel Das, Adam E. Locke, Markku Laakso, Jagadish Vangipurapu, Aki S. Havulinna, Liron Ganel, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, and Department of Biochemistry and Developmental Biology

Subjects
Male, Genome-wide association study, QH426-470, Genome, Genome-wide association studies, 0302 clinical medicine, Human genetics, GENETIC-VARIANTS, Drug Discovery, Genotype, 2.1 Biological and endogenous factors, Aetiology, Exome sequencing, Genetics & Heredity, Genetics, 0303 health sciences, INSULIN SENSITIVITY, HERITABILITY, FETAL-HEMOGLOBIN, 1184 Genetics, developmental biology, physiology, Single Nucleotide, Middle Aged, Metabolic syndrome, INTERGENIC VARIANTS, Mitochondrial, Phenotype, HBS1L-MYB, OBESITY, Medicine, Molecular Medicine, Female, Primary Research, Sequence Analysis, Adult, Mitochondrial DNA, DNA Copy Number Variations, Locus (genetics), PHENOTYPES, Biology, DNA, Mitochondrial, Polymorphism, Single Nucleotide, DNA sequencing, 03 medical and health sciences, Proto-Oncogene Proteins c-myb, Human genome sequencing, GTP-Binding Proteins, Exome Sequencing, Mendelian randomization, Humans, Cell Lineage, Genetic Predisposition to Disease, Polymorphism, Mitochondrial content, Molecular Biology, Gene, Metabolic and endocrine, 030304 developmental biology, Aged, FATTY LIVER-DISEASE, Human Genome, Membrane Proteins, DNA, Sequence Analysis, DNA, Mendelian Randomization Analysis, FINNISH FAMILIES, Genome, Mitochondrial, 3111 Biomedicine, Apoptosis Regulatory Proteins, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718). Results We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 × 10−8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 × 10−8), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 × 10−21) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition. Conclusion These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.

Published
2021

20. Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Author

Martin I. Jones, Joseph D. Szustakowski, Giorgio Sirugo, Lukas Habegger, Adam J. Mansfield, Will Salerno, Joshua D. Backman, Athanasios Kousathanas, David J. Carey, Yi-Pin Lai, James F. Wilson, Alison M. Meynert, Anne E. Justice, Alexander H. Li, Jack A. Kosmicki, Anthony Marcketta, Sándor Szalma, Shane McCarthy, A. R. Shuldiner, A. Baras, Daniel J. Rader, Michael N. Cantor, Ashish Yadav, Manuel A. R. Ferreira, F. S. P. Kury, Konrad Rawlik, Loukas Moutsianas, Gonçalo R. Abecasis, Susan P. Walker, Xing Chen, Albert Tenesa, Paul Nioi, Adam E. Locke, Guillaume Butler-Laporte, E. N. Smith, Richard H Scott, Gundula Povysil, Joseph B. Leader, Lauren Gurski, Dorota Pasko, Marylyn D. Ritchie, A. Cordova-Palomera, Kyoko Watanabe, Colm O'Dushlaine, A. O'Neill, Tomoko Nakanishi, Erola Pairo-Castineira, Xiuwen Zheng, Emily Wong, Jeffrey G. Reid, Slavé Petrovski, Julie E. Horowitz, Anurag Verma, Justin W. Davis, Dylan Sun, Sahar Esmaeeli, Heiko Runz, Quanli Wang, John D. Overton, Shareef Khalid, Tooraj Mirshahi, Evan Maxwell, Mark J. Caulfield, Mark Lathrop, Olympe Chazara, Deepika Sharma, David Goldstein, Jonathan Marchini, Xiaodong Bai, Suganthi Balasubramanian, Krzysztof Kiryluk, Nilanjana Banerjee, Rouel Lanche, J. B. Richards, Hyun Min Kang, J. K. Baillie, Yunfeng Huang, Sean O'Keeffe, Erika Kvikstad, Margaret M. Parker, and Joelle Mbatchou

Subjects
Male, 0301 basic medicine, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Biology, 03 medical and health sciences, Current sample, 0302 clinical medicine, Data sequences, Report, Exome Sequencing, Genetics, Humans, Exome, Genetic Predisposition to Disease, 030212 general & internal medicine, Gene, Genetics (clinical), SARS-CoV-2, COVID-19, Prognosis, Hospitalization, 030104 developmental biology, Sample Size, Multiple comparisons problem, Susceptibility locus, Female, Interferons
Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

Published
2021

21. Association of structural variation with cardiometabolic traits in Finns

Author

Nathan O. Stitziel, Alexandra J. Scott, Allison A. Regier, Chul Joo Kang, Aki S. Havulinna, Lei Chen, Colby Chiang, Charleston W. K. Chiang, Liron Ganel, Aarno Palotie, Shuangjia Lu, Nelson B. Freimer, Erica P. Young, Ryan Christ, Johanna Kuusisto, Ira M. Hall, Xinxin Wang, Adam E. Locke, Indraniel Das, David E. Larson, Krishna L. Kanchi, Samuli Ripatti, Haley J. Abel, Michael Boehnke, and Markku Laakso

Subjects
Male, Genome-wide association study, Medical and Health Sciences, 0302 clinical medicine, Genotype, Pyruvic Acid, 2.1 Biological and endogenous factors, Copy-number variation, Aetiology, Promoter Regions, Genetic, Genetics (clinical), Exome sequencing, Finland, Genetics, Genetics & Heredity, 0303 health sciences, Genome, High-Throughput Nucleotide Sequencing, Biological Sciences, Finnish population, Phenotype, Cholesterol, Cardiovascular Diseases, Female, cardiometabolic traits, Human, DNA Copy Number Variations, Serum Albumin, Human, Biology, Quantitative trait locus, Article, Structural variation, Mitochondrial Proteins, Promoter Regions, 03 medical and health sciences, Genetic, Humans, Alleles, Serum Albumin, 030304 developmental biology, Genetic association, genome-wide association study, Genome, Human, Human Genome, structural variation, Pyruvate Dehydrogenase (Lipoamide)-Phosphatase, Genomic Structural Variation, 030217 neurology & neurosurgery
Abstract

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47× 10-54) and is also associated with increased levels of total cholesterol (p = 1.22× 10-28) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81× 10-21) and alanine (p = 6.14× 10-12) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24× 10-10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53× 10-35). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

Published
2021

22. Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

Author

Matthew Solomonson, Michael Conlon O'Donovan, Nancy L. Pedersen, Faith Dickerson, Eli A. Stahl, Neil Risch, Catherine Schaefer, Laura J. Scott, René S. Kahn, Duncan S. Palmer, Derek W. Morris, Claire Churchhouse, Xiaoming Jia, James T.R. Walters, Andrew M. McIntosh, Chia-Yen Chen, Michael John Owen, Arianna Di Florio, Lina Jonsson, Benjamin M. Neale, Roel A. Ophoff, Annabel Vreeker, Tarjinder Singh, Douglas Blackwood, Nicholas John Craddock, Jordan W. Smoller, Ian Jones, Weiqing Wang, Peter P. Zandi, Marco P. Boks, Fernando S. Goes, Lisa Jones, Robert H. Yolken, Mikael Landén, David Curtis, Danielle Posthuma, Andreas Reif, David St Clair, Sinéad B. Chapman, Nicholas A. Watts, Rolf Adolfsson, Adam E. Locke, Aiden Corvin, Nick Bass, Daniel P. Howrigan, and Andrew McQuillin

Subjects
Genetics, business.industry, Schizophrenia, Medicine, Risk gene, Genome-wide association study, Bipolar disorder, business, medicine.disease, Exome, Gene, GSK3B, Exome sequencing
Abstract

Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA,AKAP11emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06,P= 2.83 × 10−9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.

Published
2021

23. A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Author

Lawrence S. Phillips, Anurag Verma, Todd L. Edwards, Kate Townsend Creasy, Nadim Mahmud, Shweta Ramdas, Rotonya M. Carr, Elisabetta Manduchi, Yii-Der Ida Chen, Saiju Pyarajan, Sumitra Muralidhar, Ruey-Kang Chang, Mary E. Haas, Michelle T. Long, Scott M. Damrauer, Struan F.A. Grant, Joseph Brancale, Marcus B. Jones, Luca A. Lotta, Xiaohui Li, Jing He, Yedidya Saiman, Jennifer Lee, Dipender Gill, Adam E. Locke, Jonas B. Nielsen, Nicholas J. Hand, Peter D. Reaven, Jennifer E. Huffman, Ronald M. Krauss, Marijana Vujkovic, Aris Baras, Philip S. Tsao, Jie Yao, Christopher D. Brown, Ching-Ti Liu, Yan V. Sun, J. Michael Gaziano, Amit Khera, Themistocles L. Assimes, Naga Chalasani, Daniel J. Rader, Henry R. Kranzler, Jerome I. Rotter, Katherine A. Ryan, James B. Meigs, Jingyi Tan, Derek Klarin, Danish Saleheen, Brent A. Neuschwander-Tetri, Carolin V. Schneider, Lisa Bastarache, Scott L. DuVall, Henry J. Lin, Benjamin F. Voight, Catherine Tcheandjieu, Niek Verweij, Donald R. Miller, Arun J. Sanyal, David E. Kaplan, Silvia Vilarinho, Xiang Zhu, Kent D. Taylor, Braxton D. Mitchell, Rebecca Darlay, K. Rajender Reddy, Andrew D. Wells, Rachel L. Kember, Kimberly Lorenz, Yevgeniy Gindin, Kyung Min Lee, Ayush Giri, Kyong-Mi Chang, Matthew J. Budoff, Jie Huang, Kelly Cho, Christopher J. O'Donnell, Chuhan Chung, Joseph Park, Marina Serper, Peter W.F. Wilson, Quentin M. Anstee, Ann K. Daly, Walter R Witschey, Julie Lynch, Rob P Meyers, Heather J. Cordell, Matthew T. MacLean, Xiuqing Guo, and Jeffrey B. Schwimmer

Subjects
medicine.medical_specialty, business.industry, Locus (genetics), Genome-wide association study, medicine.disease, Chronic liver disease, Gastroenterology, Internal medicine, Radiological weapon, Nonalcoholic fatty liver disease, Medicine, Stage (cooking), Alanine aminotransferase, business, Proxy (statistics)
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic alanine aminotransferase elevation (cALT) without other liver diseases, we performed a trans-ancestry genome-wide association study in the Million Veteran Program including 90,408 cALT cases and 128,187 controls. In the Discovery stage, seventy-seven loci exceeded genome-wide significance – including 25 without prior NAFLD or ALT associations – with one additional locus identified in European-American-only and two in African-American-only analyses (P-8). External replication in cohorts with NAFLD defined by histology (7,397 cases, 56,785 controls) or liver fat extracted from radiologic imaging (n=44,289) validated 17 SNPs (P-4) of which 9 were novel (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH, and IFI30). Pleiotropy analysis showed that 61 of 77 trans-ancestry and all 17 validated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

Published
2021

24. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Author

Marijana, Vujkovic, Shweta, Ramdas, Kim M, Lorenz, Xiuqing, Guo, Rebecca, Darlay, Heather J, Cordell, Jing, He, Yevgeniy, Gindin, Chuhan, Chung, Robert P, Myers, Carolin V, Schneider, Joseph, Park, Kyung Min, Lee, Marina, Serper, Rotonya M, Carr, David E, Kaplan, Mary E, Haas, Matthew T, MacLean, Walter R, Witschey, Xiang, Zhu, Catherine, Tcheandjieu, Rachel L, Kember, Henry R, Kranzler, Anurag, Verma, Ayush, Giri, Derek M, Klarin, Yan V, Sun, Jie, Huang, Jennifer E, Huffman, Kate Townsend, Creasy, Nicholas J, Hand, Ching-Ti, Liu, Michelle T, Long, Jie, Yao, Matthew, Budoff, Jingyi, Tan, Xiaohui, Li, Henry J, Lin, Yii-Der Ida, Chen, Kent D, Taylor, Ruey-Kang, Chang, Ronald M, Krauss, Silvia, Vilarinho, Joseph, Brancale, Jonas B, Nielsen, Adam E, Locke, Marcus B, Jones, Niek, Verweij, Aris, Baras, K Rajender, Reddy, Brent A, Neuschwander-Tetri, Jeffrey B, Schwimmer, Arun J, Sanyal, Naga, Chalasani, Kathleen A, Ryan, Braxton D, Mitchell, Dipender, Gill, Andrew D, Wells, Elisabetta, Manduchi, Yedidya, Saiman, Nadim, Mahmud, Donald R, Miller, Peter D, Reaven, Lawrence S, Phillips, Sumitra, Muralidhar, Scott L, DuVall, Jennifer S, Lee, Themistocles L, Assimes, Saiju, Pyarajan, Kelly, Cho, Todd L, Edwards, Scott M, Damrauer, Peter W, Wilson, J Michael, Gaziano, Christopher J, O'Donnell, Amit V, Khera, Struan F A, Grant, Christopher D, Brown, Philip S, Tsao, Danish, Saleheen, Luca A, Lotta, Lisa, Bastarache, Quentin M, Anstee, Ann K, Daly, James B, Meigs, Jerome I, Rotter, Julie A, Lynch, Daniel J, Rader, Benjamin F, Voight, and Kyong-Mi, Chang

Subjects
Non-alcoholic Fatty Liver Disease, Genetics, Intracellular Signaling Peptides and Proteins, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Humans, Membrane Proteins, Alanine Transaminase, Lipase, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10(−8)). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10(−4)), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

Published
2020

25. Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

Author

Marie V. Coignet, Dylan Sun, Lukas Habegger, Evan Maxwell, Daniel J. Rader, David J. Carey, Katherine A. Siminovitch, Giorgio Sirugo, Anne E. Justice, Joelle Mbatchou, Eli A. Stahl, Gonçalo R. Abecasis, Alexander H. Li, David A. Turissini, Adam E. Locke, Kristin A. Rand, Aris Baras, Joseph B. Leader, Genevieve H.L. Roberts, Ahna R. Girshick, Deepika Sharma, Nilanjana Banerjee, Fabricio S. P. Kury, John D. Overton, Shane McCarthy, Jonathan Marchini, Xiaodong Bai, Eurie L. Hong, Rouel Lanche, Amy Damask, Ashish Yadav, Raghavendran Partha, Shannon R. McCurdy, Miao Zhang, Suganthi Balasubramanian, Hyun Min Kang, Anurag Verma, Marcus B. Jones, Marylyn D. Ritchie, Colm O'Dushlaine, Manuel A. R. Ferreira, Adam J. Mansfield, Anthony Marcketta, Joshua D. Backman, Alan R. Shuldiner, Michael N. Cantor, Tooraj Mirshahi, Lee Dobbyn, Spencer C. Knight, William J Salerno, Harenda Guturu, Jeffrey G. Reid, Julie E. Horowitz, Lauren Gurski, Danny S. Park, Kyoko Watanabe, Catherine A. Ball, Asher K. Haug Baltzell, and Jack A. Kosmicki

Subjects
2019-20 coronavirus outbreak, Increased risk, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Genetic variants, MEDLINE, Severe disease, Medicine, Bioinformatics, business
Abstract

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5x10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

Published
2020

26. Association of Structural Variation with Cardiometabolic Traits in Finns

Author

David E. Larson, Allison A. Regier, Aarno Palotie, Shuangjia Lu, Nelson B. Freimer, Colby Chiang, Aki S. Havulinna, Markku Laakso, Xinxin Wang, Lei Chen, Erica P. Young, Adam E. Locke, Ryan Christ, Samuli Ripatti, Charleston W. K. Chiang, Nathan O. Stitziel, Liron Ganel, Johanna Kuusisto, Indraniel Das, Alexandra J. Scott, Ira M. Hall, Michael Boehnke, Chul Joo Kang, Krishna L. Kanchi, and Haley J. Abel

Subjects
Whole genome sequencing, Genetics, 0303 health sciences, Biology, Quantitative trait locus, Phenotype, Structural variation, 03 medical and health sciences, 0302 clinical medicine, Genotype, Copy-number variation, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology, Genetic association
Abstract

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low frequency SVs for association with 116 quantitative traits, and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including two novel loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB gene promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p=1.47×10−54), and is also associated with increased levels of total cholesterol (p=1.22×10−28) and 14 additional cholesterol-related traits, and (2) a multiallelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p=4.81×10−21) and alanine (p=6.14×10−12) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs), and one linking recurrent HP gene deletion and cholesterol levels (p=6.24×10−10), which was also found to be strongly associated with increased glycoprotein level (p=3.53×10−35). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

Published
2020

27. A catalog of associations between rare coding variants and COVID-19 outcomes

Author

Anurag Verma, Anne E. Justice, Guillaume Butler-Laporte, E. N. Smith, Lukas Habegger, Joelle Mbatchou, Susan P. Walker, Albert Tenesa, Joseph D. Szustakowski, Konrad Rawlik, Dylan Sun, Loukas Moutsianas, Shane McCarthy, Richard H Scott, Aris Baras, Evan Maxwell, Aldo Cordova-Palomera, Tooraj Mirshahi, Dorota Pasko, David J. Carey, Sahar Esmaeli, Adam J. Mansfield, Quanli Wang, Jeffrey S. Reid, Nilanjana Banerjee, Joshua D. Backman, Athanasios Kousathanas, Ashish Yadav, Mark J. Caulfield, Alison M. Meynert, Rouel Lanche, Jack A. Kosmicki, James F. Wilson, J. Brent Richards, Heiko Runz, Gonçalo R. Abecasis, Adam E. Locke, Justin W. Davis, Mark Lathrop, Alan R. Shuldiner, Lauren Gurski, J Kenneth Baillie, Michael N. Cantor, David Goldstein, John D. Overton, Kyoko Watanabe, Amanda O'Neill, Yunfeng Huang, Jonathan Marchini, Xiaodong Bai, Krzysztof Kiryluk, Slavé Petrovski, Sean O'Keeffe, Erika Kvikstad, Anthony Marcketta, Margaret M. Parker, Giorgio Sirugo, Julie E. Horowitz, Emily Wong, Olympe Chazara, Paul Nioi, Manuel A. R. Ferreira, Sándor Szalma, Joseph B. Leader, Shareef Khalid, William J Salerno, Deepika Sharma, Tomoko Nakanishi, Marcus B. Jones, Gundula Povysil, Marylyn D. Ritchie, Colm O'Dushlaine, Xiuwen Zheng, Daniel J. Rader, Suganthi Balasubramanian, Hyun Min Kang, Yi-Pin Lai, Alexander H. Li, Xing Chen, and Erola Pairo-Castineira

Subjects
Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Genome-wide association study, medicine.disease_cause, Biobank, Article, Genetic association analysis, Immunology, Multiple comparisons problem, Medicine, business, Gene, Coronavirus
Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable athttps://rgc-covid19.regeneron.com.

Published
2020

28. Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences

Author

Nelson B. Freimer, Chul Joo Kang, Aki S. Havulinna, Aarno Palotie, Samuli Ripatti, Michael Boehnke, Nathan O. Stitziel, Charleston W. K. Chiang, Adam E. Locke, Ira M. Hall, Lei Chen, David E. Larson, Ryan Christ, Indraniel Das, Johanna Kuusisto, Markku Laakso, Allison A. Regier, Erica Young, Liron Ganel, Jagadish Vangipurapu, Krishna L. Kanchi, and Haley J. Abel

Subjects
Genetics, 0303 health sciences, education.field_of_study, Mitochondrial DNA, Population, Locus (genetics), Biology, medicine.disease, Genome, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, medicine, Metabolic syndrome, education, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

Mitochondrial copy number is known to vary among humans and across tissues, and a population-based study of mitochondrial genome copy number (MT-CN) in blood – as estimated from genome sequencing data – observed strong (∼54%) heritability. However, the genetic causes and phenotypic consequences of MT-CN variation in humans are not well-studied. Here, we studied MT-CN variation in blood-derived DNA from 19,184 Finnish individuals with deep cardiometabolic trait measurements using a combination of whole genome (N = 4,163) and exome sequencing (N = 19,034) data as well as imputed array genotypes (N = 17,718). We confirmed that MT-CN in blood is highly heritable (31% by GREML). We identified two loci in the nuclear genome that are significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6×10−8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMB1M1 gene (P = 3.0×10−8), which has been reported to protect against non-alcoholic fatty liver disease in model organisms. We also found that MT-CN is strongly associated with insulin levels (P = 2.0×10−21), fat mass (P = 4.5×10−16), and other related traits. Using a Mendelian randomization framework, we constructed a genetic instrument for MT-CN using penalized regression with adjustment for potentially confounding covariates and found a significant association with insulin levels, which suggests that our MT-CN measurement in blood may be causally related to metabolic syndrome. Finally, we computed our genetic instrument in UK Biobank participants and tested it against a set of cell count and cardiometabolic traits. We found significant associations between MT-CN and both neutrophil and platelet counts (P = 1.8×10−8 and P = 1.2×10−3). While the association between MT-CN and metabolic syndrome traits was replicated in the UK Biobank, adjusting for cell counts largely eliminated these signals, suggesting that MT-CN is actually a proxy measurement for neutrophil and platelet counts in its effect on metabolic syndrome. Taken together, these results suggest that measurements of MT-CN in blood-derived DNA may primarily reflect differences in cell-type composition, and that these differences may be causally linked to insulin and related traits. Author summary The number of mitochondria per cell is variable between tissues and between individuals, and prior studies have shown that mitochondrial genome copy number in blood (MT-CN) – as estimated indirectly from sequencing of blood-derived DNA – is a genetically determined trait that varies among humans. We studied genetic data from approximately 19,000 Finnish individuals and showed that MT-CN is significantly associated with insulin and related metabolic traits, providing evidence that MT-CN levels play a role in determining these traits. Consistent with a previous study, we showed that genetics play a significant role in determining blood-derived MT-CN. We also found new evidence linking several regions of the genome to MT-CN, including a gene known to be associated with non-alcoholic fatty liver disease. Finally, we found that in the link between blood-derived MT-CN and metabolic syndrome, MT-CN likely represents the relative quantities of circulating immune cells, providing further evidence for the role of inflammation in metabolic syndrome.

Published
2020

29. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author

Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris

Subjects
0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Published
2020

30. Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences

Author

Sarah M Brotman, Chelsea K. Raulerson, Laura J. Scott, Francis S. Collins, Maren E Cannon, James P. Davis, Hannah J Perrin, Christian Fuchsberger, Karen L. Mohlke, Päivi Pajukanta, Cassandra N. Spracklen, Narisu Narisu, Johanna Kuusisto, Ying Wu, Apoorva K Iyengar, Ryan P. Welch, Kevin W Currin, Markku Laakso, Aaron T Crain, Heather M. Stringham, Yun Li, Adam E. Locke, Anne U. Jackson, Michael Boehnke, and Swarooparani Vadlamudi

Subjects
Male, Cancer Research, Heredity, Physiology, Peptide Hormones, Genome-wide association study, QH426-470, Regulatory Sequences, Nucleic Acid, Biochemistry, 0302 clinical medicine, Cell Signaling, Gene Frequency, Immune Physiology, Medicine and Health Sciences, Genetics (clinical), Genetics, Metabolic Syndrome, 0303 health sciences, Innate Immune System, Genomics, Cadherins, DNA-Binding Proteins, Genetic Mapping, Phenotype, Adipose Tissue, Cytokines, Allelic heterogeneity, Adiponectin, Genomic Signal Processing, Research Article, Signal Transduction, Immunology, DNA transcription, Quantitative Trait Loci, Locus (genetics), Quantitative trait locus, Biology, Genome Complexity, Polymorphism, Single Nucleotide, 03 medical and health sciences, Adipokines, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Alleles, 030304 developmental biology, Genetic association, Haplotype, Biology and Life Sciences, Computational Biology, Human Genetics, Cell Biology, Molecular Development, Genome Analysis, Hormones, Introns, Haplotypes, Genetic Loci, Immune System, Expression quantitative trait loci, Insulin Receptor Substrate Proteins, Gene expression, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study, Transcription Factors
Abstract

Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2, Author summary Many DNA variants affect common human traits, and distinct variants can have different effects on the function or expression level of the same gene. We identified variants associated with levels of adiponectin, a hormone involved in glucose regulation. Among these variants, we specifically studied the sets of variants located near two genes, ADIPOQ and CDH13, to determine how the variants affect gene expression or function. We focused on sets of variants that can be inherited together but are not always inherited together. Of the variants associated with adiponectin and located near ADIPOQ, one set were also associated with higher expression levels of the protein-coding ADIPOQ gene and a nearby non-coding gene, a second set of variants were associated with lower levels of the ADIPOQ-AS1 antisense gene, and additional variants changed the amino acid sequence or size of the adiponectin protein. Our examples show the benefits of identifying multiple sets of trait-associated variants in the same DNA region. These variants explain more trait variation, help identify genes that affect the trait, and guide studies of gene regulation and biological processes.

Published
2020

31. Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

Author

Merete Nordentoft, Eija Hämäläinen, Anders D. Børglum, Benjamin M. Neale, Philip R. Nielsen, Christina M. Hultman, Andrea Byrnes, Indraniel Das, Josep M. Mercader, Veikko Salomaa, Jarmo Körkkö, Preben Bo Mortensen, Seyedeh M. Zekavat, Francesco Lescai, Manuel A. Rivas, Adam E. Locke, Markku Laakso, Jason Flannick, Wesley K. Thompson, Mitja I. Kurki, Olli Pietilainen, Aarno Palotie, Claire Churchhouse, Andrea Ganna, David M. Hougaard, Daniel G. MacArthur, Samuli Ripatti, Sekar Kathiresan, Jonas Bybjerg-Grauholm, Patrick Sullivan, Alicia R. Martin, Ole Mors, Miriam S. Udler, Konrad J. Karczewski, Jessica Alföldi, Jukka S. Moilanen, Thomas Werge, Namrata Gupta, Outi Kuismin, F. Kyle Satterstrom, Connor A. Emdin, Mark J. Daly, Aki S. Havulinna, Elmo Saarentaus, Institute for Molecular Medicine Finland, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Aarno Palotie / Principal Investigator, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
0301 basic medicine, DISORDERS, SAMPLES, Genome-wide association study, Disease, Biology, Quantitative trait locus, Bioinformatics, DISEASE, Open Reading Frames, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Report, Databases, Genetic, Intellectual disability, Ethnicity, Genetics, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, AUTISM, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, GENERAL-POPULATION, RISK, 0303 health sciences, MUTATIONS, 1184 Genetics, developmental biology, physiology, Proteins, medicine.disease, Phenotype, 3. Good health, GENOME, 030104 developmental biology, Schizophrenia, Mutation, Mendelian inheritance, symbols, Autism, 3111 Biomedicine, VARIANT ASSOCIATION, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Protein truncating variants (PTVs) are likely to modify gene function and have been linked to hundreds of Mendelian disorders. However, the impact of PTVs on complex traits has been limited by the available sample size of whole-exome sequencing studies (WES). Here we assemble WES data from 100,304 individuals to quantify the impact of rare PTVs on 13 quantitative traits and 10 diseases. We focus on those PTVs that occur in PTV-intolerant (PI) genes, as these are more likely to be pathogenic. Carriers of at least one PI-PTV were found to have an increased risk of autism, schizophrenia, bipolar disorder, intellectual disability and ADHD (P-value (p) range: 5x10-3-9x10-12). In controls, without these disorders, we found that this burden associated with increased risk of mental, behavioral and neurodevelopmental disorders as captured by electronic health record information. Furthermore, carriers of PI-PTVs tended to be shorter (p=2x10-5), have fewer years of education (p=2x10-4) and be younger (p=2x10-7); the latter observation possibly reflecting reduced survival or study participation. While other gene-sets derived from in vivo experiments did not show any associations with PTV-burden, gene sets implicated in GWAS of cardiovascular-related traits and inflammatory bowel disease showed a significant PTV-burden with corresponding traits, mainly driven by established genes involved in familial forms of these disorders. We leveraged population health registries from 14,117 individuals to study the phenome-wide impact of PI-PTVs and identified an increase in the number of hospital visits among PI-PTV carriers. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

Published
2018

32. EXOME SEQUENCING IN BIPOLAR DISORDER REVEALS SHARED RISK GENE AKAP11 WITH SCHIZOPHRENIA

Author

Di Florio A, Peter P. Zandi, St. Clair D, Annabel Vreeker, Mikael Landén, Daniel P. Howrigan, Laura J. Scott, Michael Conlon O'Donovan, Benjamin M. Neale, I. Jones, Weiqing Wang, N. Craddock, Fernando S. Goes, Faith Dickerson, Robert H. Yolken, Eli A. Stahl, Nicholas A. Watts, Nancy L. Pedersen, Duncan Palmer, James T.R. Walters, Neil Risch, Aiden Corvin, Lina Jonsson, Chia-Yen Chen, Adam E. Locke, D. H. R. Blackwood, Marco P. Boks, Catherine Schaefer, Tarjinder Singh, Matthew Solomonson, Derrek Morris, L. A. Jones, Andrew McQuillin, Roel A. Ophoff, Rolf Adolfsson, Danielle Posthuma, Andrew M. McIntosh, R.S. Kahn, Sinéad B. Chapman, M J Owen, Claire Churchhouse, N Bass, Xiaoming Jia, Andreas Reif, and Jordan W. Smoller

Subjects
Pharmacology, business.industry, Schizophrenia (object-oriented programming), Risk gene, Computational biology, medicine.disease, Psychiatry and Mental health, Text mining, Neurology, medicine, Pharmacology (medical), Neurology (clinical), Bipolar disorder, business, Biological Psychiatry, Exome sequencing
Published
2021

33. Interaction between the FTO gene, body mass index and depression

Author

Bertram Müller-Myhsok, Adam E. Locke, F. Tozzi, Martin Preisig, Gérard Waeber, James Rucker, Marcella Rietschel, Yuri Milaneschi, Susanne Lucae, Cathryn M. Lewis, Katherine J. Aitchison, Ana Ching-López, Sara Cohen-Woods, Ian W. Craig, Anne Farmer, Ole Mors, Gonneke Willemsen, Michael Gill, Peter Vollenweider, Gerome Breen, Michael John Owen, Stefan Kloiber, Peter McGuffin, Brenda W.J.H. Penninx, Zoltán Kutalik, Dorret I. Boomsma, Rudolf Uher, Tanguy Corre, Nicholas John Craddock, Florian Holsboer, Sven Bergmann, Wolfgang Maier, Margarita Rivera, John P. Rice, Jouke-Jan Hottenga, Darina Czamara, Christiane Wolf, Ania Korszun, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and APH - Digital Health

Subjects
0301 basic medicine, Gerontology, Oncology, Netherlands Twin Register (NTR), medicine.medical_specialty, Population, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Genome-wide association study, Comorbidity, Review, FTO gene, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Obesity, education, Depression (differential diagnoses), Alleles, 2. Zero hunger, education.field_of_study, Depressive Disorder, Major, Polymorphism, Genetic, Case-control study, nutritional and metabolic diseases, medicine.disease, Random effects model, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Psychology, Body mass index, 030217 neurology & neurosurgery
Abstract

BackgroundDepression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.AimsTo confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.MethodThe sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.ResultsIn the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β=0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO.ConclusionsThis meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.

Published
2017

34. 33 INVESTIGATING RARE PATHOGENIC/LIKELY PATHOGENIC EXONIC VARIATION IN 3,987 BIPOLAR PATIENTS

Author

Neil Risch, Xiaoming Jia, Adam E. Locke, Shaun Purcell, Laura J. Scott, Peter P. Zandi, Eli A. Stahl, Catherine Schaefer, Benjamin M. Neale, Fernando S. Goes, Duncan S. Palmer, and Weiqing Wang

Subjects
Pharmacology, Genetics, Psychiatry and Mental health, Variation (linguistics), Neurology, Pharmacology (medical), Neurology (clinical), Biology, Biological Psychiatry, Likely pathogenic
Published
2019

35. Getting to precision psychopharmacology: Combining clinical and genetic information to predict fat gain from aripiprazole

Author

Ginger E. Nicol, Y. Zhong, Michael D. Yingling, Daniel J. Müller, John W. Newcomer, Charles F. Reynolds, Benoit H. Mulsant, Timothy R. Peterson, Adam E. Locke, J. P Miller, Eric J. Lenze, and Hanadi Ajam Oughli

Subjects
Male, medicine.medical_specialty, Aripiprazole, Venlafaxine, Placebo, Weight Gain, Polymorphism, Single Nucleotide, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Absorptiometry, Photon, Randomized controlled trial, Double-Blind Method, law, Internal medicine, Medicine, Humans, Biological Psychiatry, Adiposity, Aged, Depressive Disorder, Major, business.industry, Venlafaxine Hydrochloride, Moderation, medicine.disease, Antidepressive Agents, 3. Good health, 030227 psychiatry, Clinical trial, Psychiatry and Mental health, Drug Therapy, Combination, Female, medicine.symptom, business, Treatment-resistant depression, Weight gain, 030217 neurology & neurosurgery, medicine.drug, Genome-Wide Association Study
Abstract

Introduction All atypical antipsychotics are associated with some degree of weight gain. We applied a novel statistical approach to identify moderators of aripiprazole-induced fat gain using clinical and genetic data from a randomized clinical trial (RCT) of treatment resistant depression in older adults. Materials and methods Adults aged ≥60 years with non-response to a prospective trial of venlafaxine were randomized to 12 weeks of aripiprazole augmentation (n = 91) or placebo (n = 90). Dual energy x-ray absorptiometry (DEXA) measured adiposity at baseline and 12 weeks. Independent moderators of total body fat gain were used to generate two combined multiple moderators, one including clinical data alone and one including both clinical and genetic data to characterize individuals who gained fat during aripiprazole augmentation. Results The value of the combined genetic + clinical multiple moderator (Mcg) was 0.57 [95% CI 0.46, 0.68] (effect size: 0.57), compared to the combined clinical moderator (Mc) value of 0.49 [0.34, 0.63] (effect size: 0.49). Individuals who gained adiposity in this study were more likely to be female and younger in age, have lower weight, fasting glucose and lipids at baseline and positive for the HTR2C polymorphism. Discussion These results demonstrate a combined multiple moderator approach, including both clinical and genetic moderators, can be applied to existing clinical trial data to understand adverse treatment effects. This method allowed for more specific characterization of individuals at risk for the outcome of interest. Further work is needed to identify additional genetic moderators and to validate the approach.

Published
2018

36. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author

George Dedoussis, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Gudmar Thorleifsson, Oscar H. Franco, Xueling Sim, Philippe Froguel, Symen Ligthart, Ellen M. Schmidt, Jason M. Torres, Karen L. Mohlke, Markku Laakso, Barbara Thorand, Erwin P. Bottinger, Matthias Thurner, Torben Hansen, Jerome I. Rotter, Weihua Zhang, Ching-Ti Liu, Michael Boehnke, Kristi Läll, Konstantin Strauch, Kent D. Taylor, Andrew D. Morris, Daniel R. Witte, Anna L. Gloyn, Jonathan Marchini, Andres Metspalu, Florian Kronenberg, Anubha Mahajan, Claudia Schurmann, Jennifer Kriebel, James S. Pankow, Matthias Wuttke, Valeriya Lyssenko, Jose C. Florez, Josée Dupuis, Patricia A. Peyser, Leif Groop, John C. Chambers, Torben Jørgensen, Timothy M. Frayling, Lawrence F. Bielak, Nicholas J. Wareham, Thomas Meitinger, Alena Stančáková, Vasiliki Mamakou, Cramer Christensen, Michael Preuss, Bram P. Prins, Niels Grarup, Amanda J. Bennett, Vilmantas Giedraitis, Jian'an Luan, Young-Jin Kim, Mickaël Canouil, Robert A. Scott, Kari Stefansson, Jana Nano, Donald W. Bowden, Oluf Pedersen, Cécile Lecoeur, Anna Köttgen, Jette Bork-Jensen, Francis S. Collins, Unnur Thorsteinsdottir, Naveed Sattar, Stella Trompet, Martin Ingelsson, Maggie C.Y. Ng, Jaakko Tuomilehto, Reedik Mägi, James B. Meigs, Lauren E. Petty, J. Wouter Jukema, Andrew T. Hattersley, Claudia Langenberg, Harald Grallert, Christian Gieger, Chad M. Brummett, Ian Ford, Andrew P. Morris, James P. Cook, Vibe Nylander, Sebastian Schönherr, Daniel Taliun, Xiuqing Guo, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Jennifer E. Below, Eleftheria Zeggini, Anthony Payne, Loic Yengo, Sharon L.R. Kardia, Neil R. Robertson, Abbas Dehghan, Ivan Brandslund, Erik Ingelsson, Colin N. A. Palmer, Ruth J. F. Loos, Girish N. Nadkarni, Gonçalo R. Abecasis, Adam E. Locke, Johanna Kuusisto, Lars Lind, Krista Fischer, Annette Peters, Kai-Uwe Ec Kardt, Ioanna Ntalla, Chloé Sarnowski, Mark I. McCarthy, N. William Rayner, Allan Linneberg, Sophie Hackinger, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, HUS Abdominal Center, Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Boehnke, Michael [0000-0002-6442-7754], McCarthy, Mark I [0000-0002-4393-0510], Apollo - University of Cambridge Repository, Lee Kong Chian School of Medicine (LKCMedicine), and Epidemiology

Subjects
0301 basic medicine, Male, Linkage disequilibrium, endocrine system diseases, Genome-wide association study, DISEASE, Linkage Disequilibrium, Body Mass Index, Epigenesis, Genetic, 0302 clinical medicine, Gene Frequency, High-Throughput Screening Assays/methods, European Continental Ancestry Group/genetics, Genetics & Heredity, 0303 health sciences, Chromosome Mapping, 11 Medical And Health Sciences, Functional Genomics, 3. Good health, Genetic Loci/genetics, Medical genetics, Female, Islets of Langerhans/metabolism, Life Sciences & Biomedicine, TRAITS, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Genomics, 030209 endocrinology & metabolism, PHENOTYPES, Computational biology, Biology, Polymorphism, Single Nucleotide, White People, Article, GENETIC ARCHITECTURE, Islets of Langerhans, 03 medical and health sciences, Sex Factors, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, SCORE, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, Genotyping, Allele frequency, METAANALYSIS, 030304 developmental biology, Science & Technology, IDENTIFICATION, Genome, Human, Haplotype, 06 Biological Sciences, Human genetics, Genetic architecture, High-Throughput Screening Assays, Minor allele frequency, 030104 developmental biology, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 2/epidemiology, Sample size determination, Genetic Loci, Case-Control Studies, Genome, Human/genetics, Genome-wide Association Studies, 3111 Biomedicine, Chromosome Mapping/methods, 030217 neurology & neurosurgery, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract

We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of >30,000 sequenced haplotypes. Analysis of ˜27M variants (˜21M with minor allele frequency [MAF]p−8; MAF 0.02%-50%; odds ratio [OR] 1.04-8.05), 135 not previously-implicated in T2D-predisposition. Conditional analyses revealed 160 additional distinct association signals (p−5) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5%≤MAF2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localisation of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for >80% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA>80% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease. Genome wide chip heritability accounted for 18% of T2D-risk, and individuals in the 2.5% extremes of a polygenic risk score generated from the GWAS data differed >9-fold in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.

Published
2018

37. The genetic architecture of type 2 diabetes

Author

Clement Ma, Liisa Hakaste, Claes Ladenvall, Massimo Mangino, Lars Lind, Aaron G. Day-Williams, Ryan Poplin, Thomas Schwarzmayr, Annette Peters, Thomas Meitinger, Satish Kumar, Kyong Soo Park, Ching-Yu Cheng, Farook Thameem, Kyle J. Gaulton, Olov Rolandsson, Yossi Farjoun, Neil Robertson, Mauricio O. Carneiro, Mark A. DePristo, Pierre Fontanillas, Ruth J. F. Loos, Heather M. Highland, Vilmantas Giedraitis, Gemma Buck, Fredrik Karpe, Mohammad Kamran Ikram, Alex S. F. Doney, Hae Kyung Im, Eric S. Lander, Johanna Kuusisto, Dorothée Thuillier, Denis Rybin, Jacquelyn Murphy, Benjamin M. Neale, Martina Müller-Nurasyid, Eric R. Gamazon, Johanne Marie Justesen, Tin Aung, Vincent K. L. Lam, John Danesh, Donna M. Lehman, Goo Jun, Marit E. Jørgensen, Christian Herder, Edmund Chan, Pamela J. Hicks, Todd Green, Claudia Langenberg, Yoon Shin Cho, James G. Wilson, Daniel E. Hale, Rector Arya, Giriraj R. Chandak, Juan Fernandez Tajes, Jaakko Tuomilehto, Christopher P. Jenkinson, Anders Rosengren, Torsten Lauritzen, Michael Griswold, Karen L. Mohlke, Amy J. Swift, Alena Stančáková, Christian Fuchsberger, Iksoo Huh, Nikhil Tandon, João Fadista, Christa Meisinger, Gonçalo R. Abecasis, Pål R. Njølstad, Dwaipayan Bharadwaj, Richard M. Watanabe, Shaun Purcell, Veikko Salomaa, Tim D. Spector, Paul W. Franks, Adam E. Locke, Sharon P. Fowler, Panos Deloukas, Reedik Mägi, Solomon K. Musani, Kee Seng Chia, Barbara Thorand, Soo Heon Kwak, Annemari Käräjämäki, Evelin Mihailov, John Blangero, Thomas Wieland, Christian Gieger, E. Shyong Tai, Jianjun Liu, James B. Meigs, Teemu Kuulasmaa, Martin Hrabé de Angelis, Francis S. Collins, Tim M. Strom, Tibor V. Varga, Juyoung Lee, Mark I. McCarthy, Domenico Palli, Jong-Young Lee, Benjamin Glaser, Tasha E. Fingerlin, Stephen O'Rahilly, Andrew T. Hattersley, Gil Atzmon, Manuel A. Rivas, Noël P. Burtt, Ivan Brandslund, Young-Jin Kim, Dorairaj Prabhakaran, Xu Wang, Taylor J. Maxwell, Valeriya Lyssenko, Frank B. Hu, Adolfo Correa, Khalid Shakir, Kathleen A. Jablonski, Yingchang Lu, Wei-Yen Lim, Min Jin Go, William R. Scott, Hanna E. Abboud, Leena Kinnunen, Inês Barroso, Gabriela L. Surdulescu, Peng Chen, Robert Sladek, Marju Orho-Melander, Xueling Sim, Robert A. Scott, Joanna M. M. Howson, Markku Laakso, David Altshuler, Vidya S. Farook, Harald Grallert, Janina S. Ried, Vineeta Agarwala, Philippe Froguel, Nicholas J. Wareham, Tiinamaija Tuomi, Joon Yoon, Heikki A. Koistinen, Toni I. Pollin, Heiner Boeing, Marie Loh, Nicola L. Beer, Joanne E. Curran, Lars Lannfelt, Dorota Pasko, Taesung Park, David Buck, Nir Barzilai, Stephen C. J. Parker, Michael Roden, Bok-Ghee Han, David Aguilar, Timothy Fennell, Sian-Tsung Tan, Gregory P. Wilson, Momoko Horikoshi, Cramer Christensen, Craig L. Hanis, Gilean McVean, Benjamin F. Voight, Wolfgang Rathmann, Jared Maguire, Ashok Kumar, Donald W. Bowden, Michael L. Stitzel, Yongkang Kim, Christine Blancher, Jason Carey, Min-Seok Kwon, Nicholette D. Palmer, Oluf Pedersen, Niels Grarup, Peter S. Chines, Cornelia Huth, James Scott, Torben Hansen, Konstantin Strauch, Erwin P. Bottinger, Andrew D. Morris, Anette P. Gjesing, Erik Ingelsson, Colin N. A. Palmer, Claudia H. T. Tam, Stacey Gabriel, Pablo Cingolani, Beverley Balkau, Michael Boehnke, Peter M. Nilsson, Wing-Yee So, Andrew R. Wood, Lili Milani, Ravindranath Duggirala, Qibin Qi, Mark Walker, Weiping Jia, Mark Seielstad, Narisu Narisu, Tien Yin Wong, Martijn van de Bunt, Anubha Mahajan, Davis J. McCarthy, Ann-Christine Syvänen, Jennifer Kriebel, N. William Rayner, Han Chen, Jinyan Huang, Chiea Chuen Khor, Richard N. Bergman, Shah Ebrahim, Dylan Hodgkiss, Weihua Zhang, Manjinder S. Sandhu, Richard D. Pearson, Juliana C.N. Chan, Rainer Rauramaa, Ralph A. DeFronzo, Andrew Farmer, Yoshihiko Nagai, Allan Linneberg, Herman A. Taylor, Jose C. Florez, Jaspal S. Kooner, Lori L. Bonnycastle, Jeroen R. Huyghe, Leif Groop, Joseph Trakalo, Sobha Puppala, Bong-Jo Kim, Kathleen Stirrups, Kerrin S. Small, Cecilia M. Lindgren, Jennifer E. Below, Heung Man Lee, Inga Prokopenko, Liming Liang, Timothy M. Frayling, Uzma Afzal, Mark J. Daly, Yik Ying Teo, Andrew P. Morris, Phoenix Kwan, Yvonne T. van der Schouw, Cheng Hu, Katharine R. Owen, Alisa K. Manning, Christopher J. Groves, Josée Dupuis, Ryan P. Welch, Loukas Moutsianas, Joshua D. Smith, Tanya M. Teslovich, Robert C. Onofrio, Maggie C.Y. Ng, Peter Donnelly, Tõnu Esko, Matt Neville, Bo Isomaa, Anne U. Jackson, Jette Bork-Jensen, Barry I. Freedman, Yi Chen, Danish Saleheen, Lu Qi, Laura J. Scott, Jasmina Kravic, Paul Elliott, Mette Hollensted, Carmen Navarro, Selyeong Lee, Benjamin Lehne, Thomas Illig, Nancy J. Cox, Jonathan C. Levy, George B. Grant, John C. Chambers, Adam S. Butterworth, Ronald C.W. Ma, Teresa Ferreira, John R. B. Perry, Eleftheria Zeggini, Hyun Min Kang, Loic Yengo, Eric Banks, Jae-Hoon Lee, Anna L. Gloyn, Christopher Hartl, Wei Zhao, Andres Metspalu, Keng-Han Lin, Graeme I. Bell, Jason Flannick, Torben Jørgensen, Thomas W. Blackwell, Heather M. Stringham, Olle Melander, Omri Gottesman, Other departments, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, Internal Medicine, Perry, John [0000-0001-6483-3771], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Danesh, John [0000-0003-1158-6791], Johnson, Kathleen [0000-0002-6823-3252], O'Rahilly, Stephen [0000-0003-2199-4449], Langenberg, Claudia [0000-0002-5017-7344], Sandhu, Manjinder [0000-0002-2725-142X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, PROTEIN INTERACTION NETWORKS, SUSCEPTIBILITY LOCI, Genotyping Techniques, General Science & Technology, DNA Mutational Analysis, SEQUENCING ASSOCIATION, 030209 endocrinology & metabolism, Genome-wide association study, Biology, Research Support, N.I.H, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Genetic predisposition, Journal Article, Humans, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Non-U.S. Gov't, Exome sequencing, Alleles, Genetic association, Genetics, RISK, Multidisciplinary, HERITABILITY, Research Support, Non-U.S. Gov't, COMPLEX TRAITS, Extramural, Genetic Variation, Genetic architecture, HUMAN-DISEASE, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, RARE VARIANTS, Sample Size, LOW-FREQUENCY, Imputation (genetics), Common disease-common variant, Genome-Wide Association Study
Abstract

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Published
2016

38. Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects

Author

Dhanya Ramachandran, Jennifer G. Mulle, Tracie C. Rosser, Zhen Zeng, Adam E. Locke, Roger H. Reeves, Kenneth J. Dooley, Eleanor Feingold, Cheryl L. Maslen, Michael E. Zwick, Lora J. H. Bean, David J. Cutler, Stephanie L. Sherman, Clifford L. Cua, and George T. Capone

Subjects
medicine.medical_specialty, Down syndrome, Genotype, Chromosomes, Human, Pair 21, Heart malformation, birth defect, Population, Genome-wide association study, Investigations, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, congenital heart defect, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, aneuploidy, Atrioventricular Septal Defect, education, Molecular Biology, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, trisomy, 0303 health sciences, education.field_of_study, Heart septal defect, Heart Septal Defects, Chromosome Mapping, Genetic Variation, medicine.disease, 3. Good health, Phenotype, complex trait, Case-Control Studies, Cardiology, Down Syndrome, Trisomy, Chromosome 21, Genome-Wide Association Study
Abstract

The goal of this study was to identify the contribution of common genetic variants to Down syndrome−associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome−associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.

Published
2015

39. Heterozygous Mutations of Clpb As a Newly Identified and Frequent Cause of Severe Congenital Neutropenia

Author

Julia Skokowa, Vahagn Makaryan, Peeradol Wattanasirakul, Adam E. Locke, Julia T. Warren, Audrey Anna Bolyard, Daniel C. Link, David C. Dale, David H. Spencer, and Karl Welte

Subjects
Mutation, Immunology, Cell Biology, Hematology, Biology, Neutropenia, medicine.disease_cause, medicine.disease, Biochemistry, Granulopoiesis, Haematopoiesis, medicine, Missense mutation, Congenital Neutropenia, CLPB, Exome sequencing
Abstract

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis characterized by severe chronic neutropenia from birth, premature death secondary to infectious complications, and transformation to myeloid malignancy. Although many cases of SCN are associated with mutations in ELANE, encoding the neutrophil elastase, roughly one-third of cases do not have an identifiable genetic cause. In collaboration with the Severe Chronic Neutropenia International Registry (SCNIR), we performed exome sequencing on 90 cases of congenital neutropenia. Heterozygous missense mutations of CLPB were identified in six patients with SCN. None of these patients had mutations in other genes known to cause SCN. A total of 5 different mutations were identified that clustered within the ATPase domain. Of note, all of these mutations were predicted to be functionally deleterious and had a frequency of Prior studies showed that biallelic mutations of CLPB are associated with a syndrome defined by 3-methylglutaconic aciduria (3-MGA), cataracts, neurologic disease, and variable neutropenia. In our original cohort of 6 SCN patients with heterozygous CLPB mutations, 3-MGA was not present in the three cases where urine samples were available and none had reported cataracts. In total, 3 had neurologic abnormalities (2 seizures and 1 developmental delay). Of note, the CLPB mutations present in syndromic cases were distinct from those seen in our SCN cohort, and none of the mutations in our series are biallelic. CLPB encodes for caseinolytic peptidase B, a protein implicated in protein folding in bacteria and yeast but with an unknown role in human granulopoiesis. Based on these observations, we hypothesize that CLPB is required for normal basal granulopoiesis and that the heterozygous CLPB mutations identified in our study act in a dominant-negative fashion to disrupt granulopoiesis. To test this hypothesis, two complementary genetic approaches were employed. First, we used CRISPR-Cas9 gene editing to generate null mutations in CLPB in human cord blood-derived CD34+ hematopoietic stem/progenitor cells (HSPCs). Using this approach, we are able to achieve greater than 90% editing efficiency as assessed by next generation sequencing. The genetically modified HSPCs were cultured for 14 days under conditions that promote granulocytic differentiation. Modified HSPCs were also seeded into methylcellulose cultures to measure CFU-G. The percentage and absolute number of mature granulocytes, but not early granulocytic precursors (promyelocytes and myelocytes), were significantly reduced in cultures of gene-edited cord blood CD34+ cells. Moreover, the frequency of edited cells decreases over time in our culture system indicating that CLPB-knockout cells have a competitive disadvantage. A significant decrease in CFU-G also was observed. Second, we generated lentivirus expressing all 5 of the neutropenia-associated heterozygous CLPB mutations identified in our SCN cohort (N496K, E557K, R561G, R603H, and R620C). Expression of all of these mutants (except R603H) in cord blood-derived CD34+ cells was associated with a significant decrease in mature neutrophils and corresponding increase in early granulocytic precursors. These four CLPB mutants also resulted in a decrease in CFU-G. Collectively, these data strongly suggest that heterozygous mutations of CLPB are a new cause of congenital neutropenia. Indeed, in the North American population, CLPB mutations appear to be the second most common cause of congenital neutropenia, behind ELANE mutations. Studies are underway to examine the molecular mechanisms by which mutant CLPB disrupts granulopoiesis. Disclosures Dale: Coherus: Consultancy; Beheringer/Ingelheim: Consultancy; Athelas: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; x4pharma: Consultancy, Honoraria, Research Funding.

Published
2019

40. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

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

Subjects
0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Published
2018

41. Gene-based meta-analysis of genome-wide association studies implicates new loci involved in obesity

Author

Yudi Pawitan, Tõnu Esko, Tune H. Pers, Marten A. Siemelink, Andrea Ganna, Elizabeth K. Speliotes, Kari E. North, Erik Ingelsson, Sara Hägg, Anne E. Justice, Bratati Kahali, Gerard Pasterkamp, Sander W. van der Laan, Sonja I. Berndt, Ruth J. F. Loos, Adam E. Locke, Joel N. Hirschhorn, and David P. Strachan

Subjects
medicine.medical_specialty, Genome-wide association study, Biology, Research Support, Polymorphism, Single Nucleotide, White People, Body Mass Index, Journal Article, Genetics, medicine, Humans, Genetic Predisposition to Disease, Obesity, Non-U.S. Gov't, Molecular Biology, Gene, Genetics (clinical), Genetic association, 2. Zero hunger, Research Support, Non-U.S. Gov't, Association Studies Articles, General Medicine, Genetic Loci, Meta-analysis, Cohort, Medical genetics, Female, Allelic heterogeneity, Body mass index, Genome-Wide Association Study, Meta-Analysis
Abstract

To date, genome-wide association studies (GWASs) have identified >100 loci with single variants associated with body mass index (BMI). This approach may miss loci with high allelic heterogeneity; therefore, the aim of the present study was to use gene-based meta-analysis to identify regions with high allelic heterogeneity to discover additional obesity susceptibility loci. We included GWAS data from 123 865 individuals of European descent from 46 cohorts in Stage 1 and Metabochip data from additional 103 046 individuals from 43 cohorts in Stage 2, all within the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Each cohort was tested for association between ∼2.4 million (Stage 1) or ∼200 000 (Stage 2) imputed or genotyped single variants and BMI, and summary statistics were subsequently meta-analyzed in 17 941 genes. We used the 'VErsatile Gene-based Association Study' (VEGAS) approach to assign variants to genes and to calculate gene-based P-values based on simulations. The VEGAS method was applied to each cohort separately before a gene-based meta-analysis was performed. In Stage 1, two known (FTO and TMEM18) and six novel (PEX2, MTFR2, SSFA2, IARS2, CEP295 and TXNDC12) loci were associated with BMI (P < 2.8 × 10(-6) for 17 941 gene tests). We confirmed all loci, and six of them were gene-wide significant in Stage 2 alone. We provide biological support for the loci by pathway, expression and methylation analyses. Our results indicate that gene-based meta-analysis of GWAS provides a useful strategy to find loci of interest that were not identified in standard single-marker analyses due to high allelic heterogeneity.

Published
2015

42. Contribution of copy-number variation to Down syndrome–associated atrioventricular septal defects

Author

David J. Cutler, George T. Capone, Promita Bose, Roger H. Reeves, Tracie C. Rosser, Kenneth J. Dooley, Stephanie L. Sherman, Lora J. H. Bean, Adam E. Locke, Michael E. Zwick, Clifford L. Cua, Dhanya Ramachandran, Jennifer G. Mulle, and Cheryl L. Maslen

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Down syndrome, Atrioventricular septal defects, DNA Copy Number Variations, 030204 cardiovascular system & hematology, Biology, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Ciliome, cardiovascular diseases, Atrioventricular Septal Defect, Copy-number variation, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Heart septal defect, Heart Septal Defects, Congenital heart defect, medicine.disease, Copy Number Variation, Surgery, Case-Control Studies, cardiovascular system, Cardiology, Down Syndrome
Abstract

The goal of this study was to identify the contribution of large copy-number variants to Down syndrome-associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population.Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background.Large, common copy-number variants with substantial effect sizes (OR2.0) do not account for the increased risk observed in Down syndrome-associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P0.01) and intersected more genes (P0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls.Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome-associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome-associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.

Published
2015

43. In search of rare variants: Preliminary results from whole genome sequencing of 1,325 individuals with psychophysiological endophenotypes

Author

Richard M. Myers, Shawn Levy, Eleonora Porcu, Xiaowei Zhan, Scott I. Vrieze, Hyun Min Kang, Alan Kwong, Gonçalo R. Abecasis, Adam E. Locke, Stephen M. Malone, Daniel E. Irons, William G. Iacono, Goo Jun, Giorgio Pistis, William S. Oetting, Matthew Flickinger, Matt McGue, and Uma Vaidyanathan

Subjects
Genetics, Whole genome sequencing, Endocrine and Autonomic Systems, Cognitive Neuroscience, General Neuroscience, Experimental and Cognitive Psychology, Genomics, Genome-wide association study, Genome, Neuropsychology and Physiological Psychology, Developmental Neuroscience, Neurology, 1000 Genomes Project, Psychology, Exome, Biological Psychiatry, Exome sequencing, Genetic association
Abstract

Five of the companion articles in this special issue describe genome-wide association studies (GWAS) from a fixed genotyping array with a prespecified set of 527,829 variants. Such genotyping arrays are designed primarily to capture common variants, those with a minor allele frequency, or MAF, greater than .05. The other original research article in this issue (Vrieze et al., 2014) describes an association study between the 17 putative endophenotypes and rare nonsynonymous exonic variants specifically, which are variants in coding regions that affect protein structure. In the current study, we extended these analyses by employing whole genome sequencing in an attempt to discover nearly all single nucleotide polymorphisms (SNPs) present in any given individual, including those on the GWAS and exome arrays as well as tens of millions of additional variants. Because all variants are directly measured and genotyped, this results in increased power for common variants and the ability to test rare variants throughout the entire genome on a far larger scale than the other articles in this special issue. Whole genome sequencing interrogates the entire genome to discover and accurately genotype variants from across the allelic spectrum, from private mutations possessed by a single person (or family), to common variants genotyped on typical microarrays. The past few years have seen significant advances in population genetics and characterization of rare genomic variation, which were only possible with genome sequencing technology. The 1000 Genomes Project, for example, combined exome and whole genome sequencing to discover 38 million SNPs in 1,092 individuals from 14 ancestral populations (1000 Genomes Project Consortium, 2012). The Exome Sequencing Project (Fu et al., 2013) and analogous exome sequencing projects (Nelson et al., 2012) have extensively interrogated exonic regions of the genome and characterized a wide diversity of rare coding variants. In the present study, we found 27.1 million autosomal SNPs, 21.3 million of which have minor allele frequency less than 5%. Almost none of these 21 million variants were tested in the other articles of this special issue. 1000 Genomes, Exome Sequencing Project, ENCODE, and many related projects represent breathtaking technological and analytical achievements, delivering insight into molecular biology, genomics, evolutionary history, migratory patterns, and disease biology, to name a few (Lander, 2011). Genome sequencing has been less widely used in the study of human behavior, with notable exceptions including advances in the genetics of autism (Neale et al., 2012; O’Roak et al., 2011) and schizophrenia (Fromer et al., 2014; Purcell et al., 2014). These studies employed exome sequencing, which interrogates only the exons for each of ~20,000 protein coding genes throughout the genome. The exome is an important, but small, section of the genome, comprising less than 2% of all sequence in the genome. The remainder of the genome, colorfully referred to in the past as “junk DNA,” is everything but that. Work by the ENCODE consortium (ENCODE Project Consortium, 2012) and others have verified that noncoding DNA harbors genetic variation critical to genomic function. While coding variants can affect protein structure, which is undoubtedly important, noncoding DNA can affect which, when, and how frequently genes are expressed, termed “gene regulation” more broadly. Indeed, early work suggests that a majority of disease-associated variants are in noncoding regions, with regulatory regions likely enriched for genome-wide significant variants (Maurano et al., 2012; Pickrell, 2014). Exhaustively interrogating genetic variation in coding and noncoding regions requires whole genome sequencing. In the accompanying papers in this special issue, we described a variety of genetic association studies in a sample of 4,905 individuals using different genotyping technologies to identify variants associated with 17 psychophysiological phenotypes (for an overview, see Iacono, Malone, Vaidyanathan, & Vrieze, 2014). These endophenotypes include P300 amplitude, antisaccade direction errors, startle eye blink magnitude and modulation by affective stimuli, skin conductance level and responses in a habituation paradigm, and measures of resting EEG. Although some of these endophenotypes are robust candidates, and despite the hope that endophenotypes would provide increased power to detect associated genes, the investigations described in the companion articles of this special issue yielded few significant findings. In analyses of common variants, only antisaccade error was significantly associated with an individual SNP (Vaidyanathan, Malone, Donnelly et al., 2014). Tests of rare exonic variants also produced one significant association, between a nonsynonymous SNP in PARD3 and electroencephalogram (EEG) theta power (Vrieze et al., 2014). Gene-based tests of common variants, which aggregate the effect of all SNPs within a given gene into a single score, yielded several significant associations. P3 amplitude was associated with MYEF2 (Malone, Vaidyanathan et al., 2014), EEG delta power was associated with three genes (DEFA4, DEFA6, and GABRA1; Malone, Burwell et al., 2014), antisaccade performance was associated with two genes on Chromosome 2—B3GNT7 and NCL—and the aversive difference startle modulation score was associated with the PARP14 gene on Chromosome 3. Gene-based tests of rare exonic variants yielded one significant association with the pleasant difference startle modulation score and PNPLA7 (Vrieze et al., 2014), which was not readily interpretable. The present article appears last in this special issue because it is our most comprehensive and most powerful attempt to discover novel genetic loci associated with these endophenotypes. In this article, we describe three primary analyses. First, we test for association between 27 million autosomal SNPs and each of the 17 endophenotypes in 1,706 individuals with whole genome sequences. Second, we conduct gene-based tests of nonsynonymous variants in these same 1,706 individuals. Third, we use the combination of genotype arrays and sequences to impute all 27 million variants into the full Minnesota Center for Twin and Family Research (MCTFR) sample with psychophysiological endophenotypes (N = 4,905) and conduct the same single variant and gene-based burden tests in this larger sample.

Published
2014

44. Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study

Author

Michael Boehnke, Narisu Narisu, Ryan P. Welch, Christian Fuchsberger, Pasi Soininen, Francis S. Collins, Adam E. Locke, Karen L. Mohlke, Peter S. Chines, Markku Laakso, Xueling Sim, Anne U. Jackson, James P. Davis, Antti J. Kangas, Tanya M. Teslovich, Johanna Kuusisto, Mika Ala-Korpela, Heather M. Stringham, Jeroen R. Huyghe, and School of Medicine / Clinical Medicine

Subjects
0301 basic medicine, Exome/genetics, Male, Cancer Research, Principal Component Analysis/methods, Biochemistry, Subclass, chemistry.chemical_compound, Lipid Metabolism/genetics, Gene Frequency, Cell Signaling, Genotype, Exome, European Continental Ancestry Group/genetics, Genetics (clinical), Finland, Phospholipids, Genetics, Principal Component Analysis, Triglycerides/genetics, Middle Aged, Polymorphism, Single Nucleotide/genetics, Lipids, Cholesterol, Gene Frequency/genetics, Lipid Signaling, Genome-Wide Association Study/methods, Lipoproteins/genetics, Genomic Signal Processing, Research Article, Signal Transduction, lcsh:QH426-470, Lipoproteins, Quantitative Trait Loci, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, medicine, Humans, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, Triglycerides, Cholesterol, HDL/genetics, Cholesterol, HDL, Biology and Life Sciences, Proteins, Cell Biology, medicine.disease, Lipid Metabolism, Minor allele frequency, lcsh:Genetics, 030104 developmental biology, chemistry, Lipids/genetics, Genetic Loci, Dyslipidemia, Genome-Wide Association Study
Abstract

Lipid and lipoprotein subclasses are associated with metabolic and cardiovascular diseases, yet the genetic contributions to variability in subclass traits are not fully understood. We conducted single-variant and gene-based association tests between 15.1M variants from genome-wide and exome array and imputed genotypes and 72 lipid and lipoprotein traits in 8,372 Finns. After accounting for 885 variants at 157 previously identified lipid loci, we identified five novel signals near established loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG. Four of the signals were identified with a low-frequency (0.005, published version, peerReviewed

Published
2017

45. Whole-genome sequencing coupled to imputation discovers genetic signals for anthropometric traits

Author

Graham R. S. Ritchie, Massimiliano Cocca, Anette Varbo, Nicholas J. Timpson, George Dedoussis, Michael Boehnke, Marjolein N. Kooijman, Beate St Pourcain, Yasin Memari, André G. Uitterlinden, Andrew A Crawford, Eleftheria Zeggini, Fernando Rivadeneira, Satu Männistö, Caroline L Relton, Yali Xue, Petr Danecek, Kalliope Panoutsopoulou, Albert Hofman, George Davey Smith, María Soler Artigas, Michela Traglia, Josine L. Min, Weihua Zhang, Janine F. Felix, Christopher J Hammond, Claudia Langenberg, Jie Huang, Brian R. Walker, Narinder Bansal, Nigel W. Rayner, Emanuele Di Angelantonio, Kerrin S. Small, Konstantinos Hatzikotoulas, Cecilia M. Lindgren, Alisa K. Manning, Shane A. McCarthy, Susan M. Ring, Marcus E. Kleber, Abhishek Nag, Oliver Stegle, Paul Burton, Oscar H. Franco, William R. Scott, Carolina Medina-Gomez, Valentina Iotchkova, John R. B. Perry, Alireza Moayyeri, Lavinia Paternoster, Marianne Benn, Markus Perola, Katerina Trajanoska, Inês Barroso, Audrey E. Hendricks, Cinzia Sala, Carlo Sidore, Celia M. T. Greenwood, Jeremy Schwartzentruber, Richard Durbin, Cristina Bombieri, Klaudia Walter, Wei-Yu Lin, Hashem A. Shihab, Gialuigi Zaza, Jaspal S. Kooner, Magdalena Zoledziewska, Angela Matchan, Adam S. Butterworth, Pekka Jousilahti, Julia Steinberg, Anne Tybjærg-Hansen, John P. Kemp, Daniel Suveges, Nicole Soranzo, Chris Finan, Veikko Salomaa, Ioanna Ntalla, Nicholas J. Wareham, Adam E. Locke, Vincent W. V. Jaddoe, Ioanna Tachmazidou, Daniela Toniolo, Scott Wilson, Antonella Mulas, Aliki-Eleni Farmaki, Lorraine Southam, Martin D. Tobin, Tom R. Gaunt, Zhongsheng Chen, Paolo Gasparini, Andrew P. Morris, Giovanni Gambaro, John C. Chambers, Børge G. Nordestgaard, Sarah Metrustry, Benjamin Lehne, Jian'an Luan, Giovanni Malerba, Robert A. Scott, Mark I. McCarthy, Michal Szpak, Francesco Cucca, Tim D. Spector, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, University of Helsinki, Institute for Molecular Medicine Finland, Quantitative Genetics, Tachmazidou, Ioanna, Süveges, Dániel, Min, Josine L., Ritchie, Graham R. S., Steinberg, Julia, Walter, Klaudia, Iotchkova, Valentina, Schwartzentruber, Jeremy, Huang, Jie, Memari, Yasin, Mccarthy, Shane, Crawford, Andrew A., Bombieri, Cristina, Cocca, Massimiliano, Farmaki, Aliki-Eleni, Gaunt, Tom R., Jousilahti, Pekka, Kooijman, Marjolein N., Lehne, Benjamin, Malerba, Giovanni, Männistö, Satu, Matchan, Angela, Medina-Gomez, Carolina, Metrustry, Sarah J., Nag, Abhishek, Ntalla, Ioanna, Paternoster, Lavinia, Rayner, Nigel W., Sala, Cinzia, Scott, William R., Shihab, Hashem A., Southam, Lorraine, St Pourcain, Beate, Traglia, Michela, Trajanoska, Katerina, Zaza, Gialuigi, Zhang, Weihua, Artigas, María S., Bansal, Narinder, Benn, Marianne, Chen, Zhongsheng, Danecek, Petr, Lin, Wei-Yu, Locke, Adam, Luan, Jian'An, Manning, Alisa K., Mulas, Antonella, Sidore, Carlo, Tybjaerg-Hansen, Anne, Varbo, Anette, Zoledziewska, Magdalena, Finan, Chri, Hatzikotoulas, Konstantino, Hendricks, Audrey E., Kemp, John P., Moayyeri, Alireza, Panoutsopoulou, Kalliope, Szpak, Michal, Wilson, Scott G., Boehnke, Michael, Cucca, Francesco, Di Angelantonio, Emanuele, Langenberg, Claudia, Lindgren, Cecilia, Mccarthy, Mark I., Morris, Andrew P., Nordestgaard, Børge G., Scott, Robert A., Tobin, Martin D., Wareham, Nicholas J., Burton, Paul, Chambers, John C., Smith, George Davey, Dedoussis, George, Felix, Janine F., Franco, Oscar H., Gambaro, Giovanni, Gasparini, Paolo, Hammond, Christopher J., Hofman, Albert, Jaddoe, Vincent W. V., Kleber, Marcu, Kooner, Jaspal S., Perola, Marku, Relton, Caroline, Ring, Susan M., Rivadeneira, Fernando, Salomaa, Veikko, Spector, Timothy D., Stegle, Oliver, Toniolo, Daniela, Uitterlinden, André G., Barroso, Inê, Greenwood, Celia M. T., Perry, John R. B., Walker, Brian R., Butterworth, Adam S., Xue, Yali, Durbin, Richard, Small, Kerrin S., Soranzo, Nicole, Timpson, Nicholas J., Zeggini, Eleftheria, McCarthy, Shane [0000-0002-2715-4187], Bansal, Narinder [0000-0002-6925-1719], Luan, Jian'an [0000-0003-3137-6337], Di Angelantonio, Emanuele [0000-0001-8776-6719], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Perry, John [0000-0001-6483-3771], Butterworth, Adam [0000-0002-6915-9015], Soranzo, Nicole [0000-0003-1095-3852], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, DXA trait, Lipodystrophy, next-generation whole-genome sequencing, GoT2D Consortium, LOCI, Genome-wide association study, imputation, anthropometry, DXA traits, genetic association study, UK Biobank, UK10K, Body Height, Cohort Studies, DNA Methylation, Databases, Genetic, Female, Genetic Variation, Humans, Meta-Analysis as Topic, Obesity, Physical Chromosome Mapping, Quantitative Trait Loci, Sequence Analysis, DNA, Sex Characteristics, Syndrome, United Kingdom, Anthropometry, Genome, Human, Genome-Wide Association Study, Genetics, Genetics (clinical), Settore MED/03 - GENETICA MEDICA, DISEASE, HOMEOBOX GENE, WIDE ASSOCIATION, Genetics & Heredity, Genome, 1184 Genetics, developmental biology, physiology, 11 Medical And Health Sciences, RARE VARIANTS, OBESITY, LOW-FREQUENCY, Life Sciences & Biomedicine, Sequence Analysis, arcOGEN Consortium, Human, ADULT HUMAN HEIGHT, Understanding Society Scientific Group, Computational biology, TARGETED DISRUPTION, Quantitative trait locus, Biology, Article, Databases, 03 medical and health sciences, Genetic, Genetic variation, Journal Article, UK10K Consortium, Allele, Genetic association, Whole genome sequencing, Science & Technology, SpiroMeta Consortium, DNA, 06 Biological Sciences, Sex Characteristic, 030104 developmental biology, Human genome, 3111 Biomedicine, Cohort Studie, KNOCKOUT MICE, Imputation (genetics)
Abstract

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of twelve anthropometric traits associated with height, body mass and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. Seventy-one percent of signals reside within genes and fine-mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits, and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically-relevant discoveries across the frequency spectrum.

Published
2017

46. Next-generation genotype imputation service and methods

Author

Christian Fuchsberger, Po-Ru Loh, Shawn Levy, Laura J. Scott, Alan Kwong, Gonçalo R. Abecasis, Matt McGue, Adam E. Locke, Michael Boehnke, Lukas Forer, Florian Kronenberg, Scott I. Vrieze, David Schlessinger, Francesco Cucca, William G. Iacono, Anand Swaroop, Sebastian Schönherr, Carlo Sidore, Dwight Stambolian, Sayantan Das, and Emily Y. Chew

Subjects
0301 basic medicine, Genotype, Biology, Bioinformatics, computer.software_genre, Article, 03 medical and health sciences, Genetics, Statistics::Methodology, Humans, Computer Simulation, Internet, Genotype imputation, Statistics::Applications, Extramural, Quantitative Biology::Genomics, State space reduction, 030104 developmental biology, Haplotypes, Data_GENERAL, Genome informatics, Data mining, computer, Imputation (genetics), Algorithms, Genome-Wide Association Study
Abstract

Genotype imputation is a key component of genetic association studies, where it increases power, facilitates meta-analysis, and aids interpretation of signals. Genotype imputation is computationally demanding and, with current tools, typically requires access to a high-performance computing cluster and to a reference panel of sequenced genomes. Here we describe improvements to imputation machinery that reduce computational requirements by more than an order of magnitude with no loss of accuracy in comparison to standard imputation tools. We also describe a new web-based service for imputation that facilitates access to new reference panels and greatly improves user experience and productivity.

Published
2016

47. Across-cohort QC analyses of genome-wide association study summary statistics from complex traits

Author

Matthew R. Robinson, Adam E. Locke, Peter M. Visscher, Andrew R. Wood, Loos Rjf., Guo-Bo Chen, Zhi-Xiang Zhu, Jian Yang, Naomi R. Wray, Maciej Trzaskowski, Zoltán Kutalik, Sang Hong Lee, Timothy M. Frayling, Damien C. Croteau-Chonka, Joel N. Hirschhorn, Felix R. Day, and Thomas W. Winkler

Subjects
0303 health sciences, Concordance, Genome-wide association study, Sample (statistics), Biology, computer.software_genre, Statistical power, 03 medical and health sciences, 0302 clinical medicine, Outlier, Cohort, Statistics, Data mining, computer, 030217 neurology & neurosurgery, Statistic, 030304 developmental biology, Genetic association
Abstract

Genome-wide association studies (GWASs) have been successful in discovering replicable SNP-trait associations for many quantitative traits and common diseases in humans. Typically the effect sizes of SNP alleles are very small and this has led to large genome-wide association meta-analyses (GWAMA) to maximize statistical power. A trend towards ever-larger GWAMA is likely to continue, yet dealing with summary statistics from hundreds of cohorts increases logistical and quality control problems, including unknown sample overlap, and these can lead to both false positive and false negative findings. In this study we propose a new set of metrics and visualization tools for GWAMA, using summary statistics from cohort-level GWASs. We proposed a pair of methods in examining the concordance between demographic information and summary statistics. In method I, we use the population genetics Fststatistic to verify the genetic origin of each cohort and their geographic location, and demonstrate using GWAMA data from the GIANT Consortium that geographic locations of cohorts can be recovered and outlier cohorts can be detected. In method II, we conduct principal component analysis based on reported allele frequencies, and is able to recover the ancestral information for each cohort. In addition, we propose a new statistic that uses the reported allelic effect sizes and their standard errors to identify significant sample overlap or heterogeneity between pairs of cohorts. Finally, to quantify unknown sample overlap across all pairs of cohorts we propose a method that uses randomly generated genetic predictors that does not require the sharing of individual-level genotype data and does not breach individual privacy.

Published
2015

48. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author

Laura J. Scott, Neil Robertson, Anders Hamsten, Domenico Palli, Susanne Moebus, Bernhard O. Boehm, Gunnar Sigurðsson, Paul W. Franks, C. N. A. Palmer, Sonali Pechlivanis, Katharine R. Owen, Michael E. Reschen, Sarah Edkins, Jason Carey, Christopher A. O’Callaghan, Norman Klopp, Caroline S. Fox, Petter Storm, N. William Rayner, Johan G. Eriksson, Thomas Illig, Anubha Mahajan, Erik Ingelsson, Allan Linneberg, Andrew R. Wood, Oddgeir L. Holmen, Nicola L. Beer, Mark I. McCarthy, Frank B. Hu, Peter Almgren, Heiner Boeing, Peter Donnelly, Carl Platou, Veikko Salomaa, Karl-Heinz Jöcke, Wen-Hong L. Kao, Lori L. Bonnycastle, Denis Rybin, Benjamin F. Voight, Peter Kraft, Inês Barroso, Claudia Langenberg, Teresa Ferreira, Peter Kovacs, Anne Raimondo, Christian Theil Have, Ulf de Faire, Torben Hansen, Han Chen, James B. Meigs, Timothy M. Frayling, Noël P. Burtt, Gerald Steinbach, Eric Boerwinkle, Michael Stumvoll, Stefan Gustafsson, Lars Lind, Andrew D. Morris, Alena Stančáková, Panagiotis Deloukas, Kari Stefansson, Augustine Kong, Hans A. Kestler, Andrew T. Hattersley, Beverley Balkau, Lorenzo Pasquali, Yingchang Lu, Nicola D. Kerrison, George B. Grant, Eeva Korpi-Hyövälti, Steven Wiltshire, Karl Gertow, Jorge Ferrer, Barbara Thorand, Inga Prokopenko, Matthias Blüher, Yvonne T. van der Schouw, Olga McLeod, Oluf Pedersen, Leena Peltonen, Anil Chalisey, Eleftheria Zeggini, Joseph Trakalo, Eric J.G. Sijbrands, Rainer Rauramaa, Guillaume Charpentier, Satu Männistö, Cordelia Langford, Lewin Eisele, Damiano Baldassarre, Lennart C. Karssen, Rona J. Strawbridge, Ghazala Mirza, Peter S. Chines, Roman Wennauer, Sara M. Willems, Erwin P. Bottinger, Timo Saaristo, Stéphane Cauchi, Ching-Ti Liu, Martijn van de Bunt, Valgerdur Steinthorsdottir, David Altshuler, Hyun Min Kang, Michael Boehnke, Jaakko Tuomilehto, Peter M. Nilsson, Kyle J. Gaulton, Jian'an Luan, Loic Yengo, David Couper, Reedik Mägi, Harald Grallert, Simone Wahl, Juha Saltevo, Phoenix Kwan, Cecilia M. Lindgren, Peter Lichtner, Richard N. Bergman, Andrew Crenshaw, João Fadista, Michael Roden, Annette Peters, Robert A. Scott, Unnur Thorsteinsdottir, James S. Pankow, Yeji Lee, Cornelia M. van Duijn, Samuli Ripatti, Francis S. Collins, Stéphane Lobbens, Niels Grarup, Ruth J. F. Loos, Julia Meyer, Marit E. Jørgensen, Christian Herder, Inger Njølstad, John R. B. Perry, Markus M. Nöthen, Man Li, Martina Müller-Nurasyid, Valeriya Lyssenko, Pierre Fontanillas, Michael D. Linderman, Leena Kinnunen, Jana K. Rundle, Elena Tremoli, Marilyn C. Cornelis, Tanya M. Teslovich, Todd Green, Raimund Erbel, Elisabeth M. van Leeuwen, Bengt Sennblad, Olle Melander, Sirkka Keinänen-Kiukaanniemi, Markku Laakso, Eero Lindholm, Alex S. F. Doney, Anke Tönjes, Maija Hassinen, Thomas W. Mühleisen, Gonçalo R. Abecasis, Nancy L. Pedersen, Thomas Sparsø, Johanna Kuusisto, Dorothée Thuillier, Qi Sun, Ian Dunham, Himanshu Chheda, Adam E. Locke, Philippe Froguel, Nicholas J. Wareham, Bruna Gigante, Jose C. Florez, Mozhgan Dorkhan, Omri Gottesman, Liming Liang, Anna Jonsson, Tiinamaija Tuomi, Leif Groop, Steve E. Humphries, Heikki A. Koistinen, Kristian Hveem, Astradur B. Hreidarsson, Jason Flannick, Torben Jørgensen, Clement Ma, Mattias Frånberg, Ewan Birney, Andrew P. Morris, Timo A. Lakka, Rob M. van Dam, Heather M. Stringham, Christian Gieger, Elodie Eury, Konstantin Strauch, Anna L. Gloyn, Rafn Benediktsson, Andres Metspalu, David J. Hunter, Karen L. Mohlke, Gudmar Thorleifsson, Josée Dupuis, Emmi Tikkanen, Christian Fuchsberger, Evelin Mihailov, Christopher J. Groves, Soren K. Thomsen, Tõnu Esko, Anne U. Jackson, Karin Leander, Douglas M. Ruderfer, Nikolay Oskolkov, Sekar Kathiresan, Robert Sladek, Lu Qi, Jasmina Kravic, Carmen Navarro, Epidemiology, Dermatology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Stanford Univ, Dept Genet, Stanford, CA 94305 USA [ 3 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 4 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England [ 5 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 6 ] Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England [ 7 ] Wellcome Trust Sanger Inst, Hinxton, England [ 8 ] Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England [ 9 ] Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England [ 10 ] Broad Inst Harvard & MIT, Cambridge, MA USA [ 11 ] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark [ 12 ] European Genom Inst Diabet, Lille Inst Biol, Lille, France [ 13 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 14 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany [ 15 ] German Ctr Diabet Res, Neuherberg, Germany [ 16 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 17 ] Sci Life Lab, Stockholm, Sweden [ 18 ] Stockholm Univ, Dept Numer Anal & Comp Sci, S-10691 Stockholm, Sweden [ 19 ] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany [ 20 ] Univ Ulm, Med Syst Biol, D-89069 Ulm, Germany [ 21 ] Finnish Inst Mol Med, Helsinki, Finland [ 22 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 23 ] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 24 ] deCODE Genet Amgen Inc, Reykjavik, Iceland [ 25 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 26 ] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA [ 27 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA [ 28 ] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA [ 29 ] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA [ 30 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 31 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 32 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 33 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 34 ] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA [ 35 ] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA [ 36 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 37 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 38 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 39 ] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy [ 40 ] Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France [ 41 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 42 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 43 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 44 ] Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany [ 45 ] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany [ 46 ] German Inst Human Nutr, Potsdam, Germany [ 47 ] NHGRI, US NIH, Bethesda, MD 20892 USA [ 48 ] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA [ 49 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 50 ] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA [ 51 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 52 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 53 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Ctr Diabet Res, Dundee, Scotland [ 54 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 55 ] Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Novo Nordisk Scandinavia, Malmo, Sweden [ 56 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 57 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 58 ] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland [ 59 ] Folkhalsan Res Ctr, Helsinki, Finland [ 60 ] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA [ 61 ] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA [ 62 ] CNRS, UMR 8199, Inst Biol, Lille, France [ 63 ] Univ Lille 2, Inst Pasteur, Lille, France [ 64 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 65 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 66 ] Harvard Univ, Sch Med, Boston, MA USA [ 67 ] Lund Univ, Dept Clin Sci, Malmo, Sweden [ 68 ] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden [ 69 ] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 70 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 71 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 72 ] Partner Site Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany [ 73 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway [ 74 ] UCL, Inst Cardiovasc Sci, British Heart Fdn BHF Labs, Cardiovasc Genet, London, England [ 75 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 76 ] Steno Diabet Ctr, DK-2820 Gentofte, Denmark [ 77 ] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark [ 78 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 79 ] Aalborg Univ, Fac Med, Aalborg, Denmark [ 80 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 81 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany [ 82 ] Rigshosp, Copenhagen Univ Hosp, DK-2100 Copenhagen, Denmark [ 83 ] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark [ 84 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany [ 85 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Guys & St Thomas Hosp, Genom Core Facil, Biomed Res Ctr, London, England [ 86 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 87 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 88 ] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany [ 89 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 90 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany [ 91 ] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany [ 92 ] Inst Murciano Invest Biosanitaria Virgen de la Ar, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain [ 93 ] CIBERESP, Madrid, Spain [ 94 ] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain [ 95 ] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England [ 96 ] Canc Res & Prevent Inst ISPO, Florence, Italy [ 97 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 98 ] Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 99 ] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA [ 100 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 101 ] Univ Med Ctr Utrecht, Utrecht, Netherlands [ 102 ] Iceland Heart Assoc, Kopavogur, Iceland [ 103 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 104 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 105 ] Univ Ulm, Dept Clin Chem & Cent Lab, D-89069 Ulm, Germany [ 106 ] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland [ 107 ] Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland [ 108 ] Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland [ 109 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 110 ] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England [ 111 ] European Mol Biol Lab, EBI, Hinxton, England [ 112 ] Germans Trias & Pujol Univ Hosp & Res Inst, Div Endocrinol, Badalona, Spain [ 113 ] Josep Carreras Leukaemia Res Inst, Badalona, Spain [ 114 ] CIBERDEM, Barcelona, Spain [ 115 ] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England [ 116 ] Inst Invest Biomed August Pi & Sunyer, Ctr Esther Koplowitz, Barcelona, Spain [ 117 ] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA [ 118 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 119 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 120 ] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA [ 121 ] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA [ 122 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 123 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 124 ] Netherlands Consortium Hlth Ageing, Netherlands Genom Initiat, Rotterdam, Netherlands [ 125 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 126 ] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA [ 127 ] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland [ 128 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 129 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 130 ] Univ Uppsala Hosp, Dept Med Sci, Uppsala, Sweden [ 131 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 132 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 133 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 134 ] Finnish Diabet Assoc, Tampere, Finland [ 135 ] Pirkanmaa Dist Hosp, Tampere, Finland [ 136 ] Cent Finland Cent Hosp, Dept Med, Jyvasklya, Finland [ 137 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 138 ] Univ Duisdurg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 139 ] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland [ 140 ] Univ Med Ctr Ulm, Dept Internal Med, Div Endocrinol & Diabet, Ulm, Germany [ 141 ] Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, London SW7 2AZ, England [ 142 ] Nanyang Technol Univ, Singapore 639798, Singapore [ 143 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 144 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 145 ] Univ Helsinki, Cent Hosp, Dept Med, Div Endocrinol, Helsinki, Finland [ 146 ] Minerva Fdn, Helsinki, Finland [ 147 ] Hosp Univ La Paz, Inst Invest Sanitaria, Madrid, Spain [ 148 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 149 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 150 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 151 ] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England [ 152 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 153 ] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England [ 154 ] Ctr Hosp Univ Montreal, Ctr Rech, Montreal Diabet Res Ctr, Montreal, PQ, Canada [ 155 ] McGill Univ, Montreal, PQ, Canada [ 156 ] Genome Quebec Innovat Ctr, Montreal, PQ, Canada [ 157 ] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark [ 158 ] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland [ 159 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 160 ] Univ Cambridge, Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Cambridge, England [ 161 ] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 162 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 163 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 164 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England [ 165 ] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
endocrine system diseases, Medizin, Genome-wide association study, Glucose homeostasis, WIDE ASSOCIATION, Association mapping, Non-U.S. Gov't, Genome-Wide Association Study, Regulation of gene expression, Genetics, Genetics & Heredity, LARGE-SCALE ASSOCIATION, Research Support, Non-U.S. Gov't, COMMON VARIANTS, Chromosome Mapping, 11 Medical And Health Sciences, Genomics, 3. Good health, TRANSCRIPTION FACTORS, Liver, Hepatocyte Nuclear Factor 3-beta, Medical Genetics, Life Sciences & Biomedicine, Chromatin Immunoprecipitation, endocrine system, European Continental Ancestry Group/genetics, Biology, GENOTYPE IMPUTATION, Research Support, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, N.I.H, Sykursýki, Islets of Langerhans, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, HUMAN PANCREATIC-ISLETS, GLYCEMIC TRAITS, Journal Article, SNP, Humans, Genetic Predisposition to Disease, Comparative Study, Enhancer, Medicinsk genetik, Science & Technology, Binding Sites, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Receptor, Melatonin, MT2, Extramural, Molecular Sequence Annotation, Arfgengi, 06 Biological Sciences, Genetic Predisposition to Disease/genetics, BETA-CELL, Diabetes Mellitus, Type 2/genetics, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Loci, Case-Control Studies, Gene-Environment Interaction, GLUCOSE-HOMEOSTASIS, Chromatin immunoprecipitation, Developmental Biology
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. cademy of Finland 77299 102318 10493 118065 123885 124243 129293 129680 136895 139635 211119 213506 251217 263836 Agence National de la Recherche Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques Association Diabeete Risque Vasculaire Association Francaise des Diabetiques Association of Danish Pharmacies Augustinus Foundation Becket Foundation British Diabetes Association (BDA) Research British Heart Foundation Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) City of Kuopio City of Leutkirch Copenhagen County Danish Centre for Evaluation and Health Technology Assessment Danish Council for Independent Research Danish Heart Foundation Danish Research Councils Deutsche Forschungsgemeinschaft ER 155/6-2 Diabetes Research Foundation Diabetes UK Doris Duke Charitable Foundation Erasmus Medical Center Erasmus University Estonian government SF0180142s08 European Commission ENGAGE HEALTH-F4-2007-201413 FP7-201413 FP7-245536 EXGENESIS LSHM-CT-2004-005272 FP6 LSHM_CT_2006_037197 LSHM-CT-2007-037273 C-Public Health 2004310 European Regional Development Fund Federal Ministry of Education and Research, Germany FKZ 01GI1128 FKZ 01EO1001 Federal Ministry of Health, Germany Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Society Folkhalsan Research Foundation Foundation for Life and Health in Finland Foundation for Old Servants Fredrick och Ingrid Thuring Foundation French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Region) German Center for Diabetes Research German Research Council GRK1041 German National Genome Research Network Groupe d'Etude des Maladies Metaboliques et Systemiques Health Care Centers in Vasa, Narpes and Korsholm, Finland Health Foundation Heinz Nixdorf Foundation Helmholtz Zentrum Munchen Helsinki University Central Hospital Research Foundation Hospital District of Southwest Finland Ib Henriksens Foundation IngaBritt and Arne Lundberg's Research Foundation 359 Karolinska Institutet Knut and Alice Wallenberg Foundation KAW 2009.0243 Kuopio University Hospital Lundbeck Foundation Magnus Bergvall Foundation Medical Faculty of University Duisburg-Essen Medical Research Council, UK G0000649 G0601261 Ministry for Health, Welfare and Sports, the Netherlands Ministry of Education and Culture, Finland 722 627 Ministry of Education, Culture and Science, the Netherlands Ministry of Health and Prevention, Denmark Ministry of Social Affairs and Health, Finland Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany Munich Center of Health Sciences Municipal Health Care Center and Hospital in Jakobstad, Finland municipality of Rotterdam, the Netherlands Narpes Health Care Foundation National Health Screening Service of Norway National Heart, Lung, and Blood Institute, USA HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C N01HC25195 N02HL64278 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute, USA U01HG004402 N01HG65403 National Institute for Diabetes and Digestive and Kidney Diseases, USA R01DK078616 U01DK085526 K24DK080140 R01DK073490 National Institute for Health and Welfare, Finland National Institutes of Health, USA HHSN268200625226C UL1RR025005 R01DK062370 R01DK072193 1Z01HG000024 AG028555 AG08724 AG04563 AG10175 AG08861 U01HG004399 DK58845 CA055075 DK085545 DK098032 Netherlands Genomics Initiative Netherlands Organisation for Health Research and Development Netherlands Organisation of Scientific Research NOW Investments 175.010.2005.011 911-03-012 050-060-810 Nord-Trondelag County Council Nordic Center of Excellence in Disease Genetics Norwegian Institute of Public Health Norwegian Research Council Novo Nordisk Foundation Ollquist Foundation Oxford National Institute for Health Research (NIHR) Biomedical Research Centre Paavo Nurmi Foundation Paivikki and Sakari Sohlberg Foundation Perklen Foundation Pirkanmaa Hospital District, Finland Programme Hospitalier de Recherche Clinique Programme National de Recherche sur la Diabete Research Institute for Diseases in the Elderly 014-93-015 Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center Royal Swedish Academy of Sciences Sarstedt, Germany Signe and Ane Gyllenberg Foundation Sigrid Juselius Foundation Slottery Machine Association, Finland Social Insurance Institution of Finland South OstroBothnia Hospital District state of Baden-Wurttemberg, Germany Stockholm County Council 560183 Swedish Cultural Foundation, Finland Swedish Diabetes Foundation Swedish e-science Research Center Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation Swedish Research Council SFO EXODIAB 2009-1039 521-2010-3490 521-2007-4037 521-2008-2974 ANDIS 825-2010-5983 LUDC 349-2008-6589 8691 Swedish Society of Medicine Tore Nilsson Foundation Torsten and Ragnar Soderbergs Stiftelser MT33/09 University Hospital Essen University of Tromso University College London NIHR Biomedical Research Centre UK NIHR Cambridge Biomedical Research Centre Uppsala University Uppsala University Hospital Vaasa Hospital District Velux Foundation Wellcome Trust GR072960 076113 083948 090367 090532 083270 086596 098017 095101 098051 098381

Published
2015

49. Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project

Author

Sallie B. Freeman, Claudine P. Torfs, Stuart W. Tinker, Emily G. Allen, Kenneth J. Dooley, Marjorie H. Royle, Charlotte M. Druschel, Charlotte A. Hobbs, Paul A. Romitti, Lora J. H. Bean, Adam E. Locke, and Stephanie L. Sherman

Subjects
Heart Septal Defects, Ventricular, Male, medicine.medical_specialty, Pediatrics, Down syndrome, Population, Heart Septal Defects, Atrial, Sex Factors, Internal medicine, Ethnicity, medicine, Humans, cardiovascular diseases, Atrioventricular Septal Defect, education, Genetics (clinical), Tetralogy of Fallot, education.field_of_study, Heart septal defect, business.industry, Incidence, Infant, Newborn, Odds ratio, medicine.disease, United States, Confidence interval, Cardiology, Etiology, Female, Down Syndrome, business
Abstract

Purpose: The population-based National Down Syndrome Project combined epidemiological and molecular methods to study congenital heart defects in Down syndrome. Methods: Between 2000 and 2004, six sites collected DNA, clinical, and epidemiological information on parents and infants. We used logistic regression to examine factors associated with the most common Down syndrome-associated heart defects. Results: Of 1469 eligible infants, major cardiac defects were present in 44%; atrioventricular septal defect (39%), secundum atrial septal defect (42%), ventricular septal defect (43%), and tetralogy of Fallot (6%). Atrioventricular septal defects showed the most significant sex and ethnic differences with twice as many affected females (odds ratio, 1.93; 95% confidence interval, 1.40–2.67) and, compared with whites, twice as many blacks (odds ratio, 2.06; 95% confidence interval, 1.32–3.21) and half as many Hispanics (odds ratio, 0.48; 95% confidence interval, 0.30–0.77). No associations were found with origin of the nondisjunction error or with the presence of gastrointestinal defects. Conclusions: Sex and ethnic differences exist for atrioventricular septal defects in Down syndrome. Identification of genetic and environmental risk factors associated with these differences is essential to our understanding of the etiology of congenital heart defects.

Published
2008

50. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Philippe Froguel, Pekka Jousilahti, Harry Campbell, Ellen M. Schmidt, Vasiliki Lagou, John Andrew Pospisilik, Ivana Kolcic, Igor Rudan, Mark A. Sarzynski, Brigitte Kühnel, Robin Haring, Paul Knekt, Christian Gieger, Eero Kajantie, Jian Yang, Tuomas O. Kilpeläinen, Hans L. Hillege, Niek Verweij, Sarah H Wild, Torben Hansen, Leena Taittonen, Michael Boehnke, Mark I. McCarthy, Joel N. Hirschhorn, Åsa K. Hedman, D. Timothy Bishop, James F. Wilson, Jian'an Luan, Leo-Pekka Lyytikäinen, Nita G. Forouhi, Mark Walker, Elodie Eury, Konstantin Strauch, Aroon D. Hingorani, Nam H. Cho, Peter Vollenweider, Erkki Vartiainen, Jong-Young Lee, Fredrik Karpe, Jiali Han, Joanne M. Jordan, Chen Lu, Henri Wallaschofski, Anna A. E. Vinkhuyzen, Alan R. Shuldiner, David J. Hunter, Mario Falchi, Aron S. Buchman, Caroline S. Fox, Robert A. Scott, Chan Soo Shin, Fernando Rivadeneira, Zari Dastani, Veikko Salomaa, Weihua Zhang, Rui Li, John C. Chambers, Thorkild I. A. Sørensen, André G. Uitterlinden, David A. Bennett, Marianna Sanna, Claire Bellis, Lars Bertram, Karl Michaëlsson, Yingchang Lu, Marie Loh, Loic Yengo, Bok-Ghee Han, Priya Srikanth, Laura Pascoe, Peter Wagner, Philip L. De Jager, Oscar H. Franco, Yongmei Liu, Stavroula Kanoni, Simone Gärtner, Ruth J. F. Loos, Eric E. Schadt, Claes Ohlsson, Cornelia M. van Duijn, Jorma S. A. Viikari, Stephan J. L. Bakker, Tamara B. Harris, Pirro G. Hysi, Samuli Ripatti, John R. B. Perry, Stefan A. Czerwinski, Tune H. Pers, Angela Döring, Ghazaleh Fatemifar, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Carrie M. Nielson, Claudia Langenberg, Carolina Medina-Gomez, Mike A. Nalls, Erik Ingelsson, Barbara McKnight, Niels Grarup, L. Adrienne Cupples, Torben Jørgensen, Satu Männistö, Jianbo Na, Cristen J. Willer, Tuomo Rankinen, Irene Mateo Leach, Cecilia M. Lindgren, Marie-Claude Vohl, Ryan W. Walker, Yun Ju Sung, Joanne M. Murabito, Natasja M. van Schoor, Mika Kivimäki, Nicholas J. Wareham, Lei Yu, Markku Laakso, Julia A. Newton Bishop, Pim van der Harst, Qibin Qi, Veronique Bataille, Clive Osmond, Alan F. Wright, Audrey C. Choh, Charles C. White, Felix R. Day, Ron T. Gansevoort, Tiina Laatikainen, Ozren Polasek, Johan G. Eriksson, Mark M. Iles, Dena G. Hernandez, Meena Kumari, Dmitry Shungin, Jeffrey R. O'Connell, Joseph M. Zmuda, Antti Jula, Hyung Jin Choi, Albert Hofman, Steven R. Cummings, Youfang Liu, Vilmundur Gudnason, J. Brent Richards, Michael Stumvoll, Ayse Demirkan, Teresa Ferreira, Rosalie A. M. Dhonukshe-Rutten, Rahel Eckardt, Lude Franke, Karen L. Mohlke, Uzma Afzal, Kijoung Song, Till Ittermann, Janina S. Ried, Allan Linneberg, Nicholas D. Hastie, Laticia Oozageer, Johanna Kuusisto, John Blangero, Amélie Bonnefond, Panos Deloukas, Andrew P. Morris, Oluf Pedersen, Adam E. Locke, Emmi Tikkanen, Veronique Vitart, Aki S. Havulinna, Olli T. Raitakari, Inga Prokopenko, Peter Lichtner, Harm-Jan Westra, Katja Borodulin, Teemu Kuulasmaa, Lars Lind, Bradford Towne, Christine G. Lee, Mika Kähönen, Anke W. Enneman, Terrence S. Furey, Treva Rice, Abbas Dehghan, Jaspal S. Kooner, Dabeeru C. Rao, Terrence Forrester, Jing Hua Zhao, Xin Li, Mary F. Feitosa, Melissa E. Garcia, Tian Liu, Aarno Palotie, Eric S. Orwoll, Reedik Mägi, Daniel S. Evans, Elisabeth Widen, Tim D. Spector, Caroline Hayward, Annette Peters, Markku Heliövaara, Harald Grallert, Niina Eklund, Robert C. Kaplan, Ilja Demuth, Luigi Ferrucci, Kati Kristiansson, Amy Luke, Tõnu Esko, Ken K. Ong, Gregory J. Tranah, Angelo Tremblay, Ben A. Oostra, Stefan Gustafsson, Zhihong Zhu, Nina Smolej Narančić, Cameron D. Palmer, William R. Scott, Alexander Teumer, Anne U. Jackson, Markus Perola, Toshiko Tanaka, Lavinia Paternoster, Henry Völzke, Terho Lehtimäki, Dominik Spira, Karin M. A. Swart, Louis Pérusse, Matthias Blüher, Jari Lahti, M. Carola Zillikens, Kari E. North, Yvonne Boettcher, Douglas P. Kiel, Bamidele O. Tayo, Elisabeth Steinhagen-Thiessen, Diana L. Cousminer, Joanne E. Curran, Peter Kovacs, David M. Evans, Claude Bouchard, Alena Stančáková, Seppo Koskinen, Jack W. Kent, Alexander W. Drong, Massimo Mangino, Frédéric Fumeron, Richard S. Cooper, Juha Karjalainen, Nathalie van der Velde, Martin L. Buchkovich, Stéphane Lobbens, Cristina Menni, Anubha Mahajan, Nele Friedrich, Anke Tönjes, Colin A. McKenzie, Tom Forsén, Anne E. Justice, Lisette C. P. G. M. de Groot, Ingrid B. Borecki, Mingfeng Zhang, Tommy Cederholm, IOO, Internal medicine, Epidemiology and Data Science, EMGO - Musculoskeletal health, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, Internal Medicine, Erasmus MC other, Epidemiology, Clinical Genetics, Institute for Molecular Medicine Finland, Clinicum, Department of General Practice and Primary Health Care, Behavioural Sciences, Samuli Olli Ripatti / Principal Investigator, Department of Public Health, Aarno Palotie / Principal Investigator, Johan Eriksson / Principal Investigator, Children's Hospital, Lastentautien yksikkö, University of Helsinki, Elisabeth Ingrid Maria Widen / Principal Investigator, Biostatistics Helsinki, Quantitative Genetics, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
0301 basic medicine, Medicin och hälsovetenskap, Drosophila melanogaster/genetics, Nutrition and Disease, General Physics and Astronomy, Genome-wide association study, Medical and Health Sciences, Body fat percentage, Voeding en Ziekte, CUTANEOUS NEVI, Mass index, Human Nutrition & Health, Adiposity, INSULIN-RESISTANCE, Multidisciplinary, body fat, cardiometabolic traits, genome-wide association study, meta-analysis, biology, Disease genetics, Leptin, Humane Voeding & Gezondheid, COMMON VARIANTS, Public Health, Global Health, Social Medicine and Epidemiology, 3. Good health, Biological sciences, Cardiovascular diseases, Drosophila melanogaster, Gene Knockdown Techniques, ENERGY-BALANCE, Medical Genetics, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Heart Diseases, 515 Psychology, Science, Quantitative Trait Loci, PROVIDES INSIGHTS, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, Article, GENETIC ARCHITECTURE, 03 medical and health sciences, MASS INDEX, Insulin resistance, Internal medicine, MD Multidisciplinary, Genetics, medicine, Life Science, Animals, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Medicinsk genetik, VLAG, Global Nutrition, Wereldvoeding, Gene Expression Regulation/physiology, C-reactive protein, Metabolic diseases, General Chemistry, ta3121, medicine.disease, Onderwijsinstituut, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Adiposity/genetics, Drosophila melanogaster/metabolism, Genome-Wide Association Study, Heart Diseases/genetics, Quantitative Trait Loci/genetics, 030104 developmental biology, Endocrinology, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, Lean body mass, IDENTIFIES COMMON
Abstract

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P, A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Published
2015

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