1. The power of genetic diversity in genome-wide association studies of lipids
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Graham, Sarah E. Clarke, Shoa L. Wu, Kuan-Han H. Kanoni, Stavroula Zajac, Greg J. M. Ramdas, Shweta Surakka, Ida and Ntalla, Ioanna Vedantam, Sailaja Winkler, Thomas W. Locke, Adam E. Marouli, Eirini Hwang, Mi Yeong Han, Sohee and Narita, Akira Choudhury, Ananyo Bentley, Amy R. Ekoru, Kenneth Verma, Anurag Trivedi, Bhavi Martin, Hilary C. and Hunt, Karen A. Hui, Qin Klarin, Derek Zhu, Xiang and Thorleifsson, Gudmar Helgadottir, Anna Gudbjartsson, Daniel F. and Holm, Hilma Olafsson, Isleifur Akiyama, Masato Sakaue, Saori Terao, Chikashi Kanai, Masahiro Zhou, Wei and Brumpton, Ben M. Rasheed, Humaira Ruotsalainen, Sanni E. and Havulinna, Aki S. Veturi, Yogasudha Feng, QiPing Rosenthal, Elisabeth A. Lingren, Todd Pacheco, Jennifer Allen and Pendergrass, Sarah A. Haessler, Jeffrey Giulianini, Franco and Bradford, Yuki Miller, Jason E. Campbell, Archie Lin, Kuang and Millwood, Iona Y. Hindy, George Rasheed, Asif Faul, Jessica D. Zhao, Wei Weir, David R. Turman, Constance and Huang, Hongyan Graff, Mariaelisa Mahajan, Anubha Brown, Michael R. Zhang, Weihua Yu, Ketian Schmidt, Ellen M. and Pandit, Anita Gustafsson, Stefan Yin, Xianyong Luan, Jian'an and Zhao, Jing-Hua Matsuda, Fumihiko Jang, Hye-Mi Yoon, Kyungheon Medina-Gomez, Carolina Pitsillides, Achilleas and Hottenga, Jouke Jan Willemsen, Gonneke Wood, Andrew R. Ji, Yingji Gao, Zishan Haworth, Simon Mitchell, Ruth E. and Chai, Jin Fang Aadahl, Mette Yao, Jie Manichaikul, Ani and Warren, Helen R. Ramirez, Julia Bork-Jensen, Jette Karhus, Line L. Goel, Anuj Sabater-Lleal, Maria Noordam, Raymond and Sidore, Carlo Fiorillo, Edoardo McDaid, Aaron F. and Marques-Vidal, Pedro Wielscher, Matthias Trompet, Stella and Sattar, Naveed Mollehave, Line T. Thuesen, Betina H. Munz, Matthias Zeng, Lingyao Huang, Jianfeng Yang, Bin Poveda, Alaitz Kurbasic, Azra Lamina, Claudia Forer, Lukas and Scholz, Markus Galesloot, Tessel E. Bradfield, Jonathan P. and Daw, E. Warwick Zmuda, Joseph M. Mitchell, Jonathan S. and Fuchsberger, Christian Christensen, Henry Brody, Jennifer A. and Feitosa, Mary F. Wojczynski, Mary K. Preuss, Michael and Mangino, Massimo Christofidou, Paraskevi Verweij, Niek and Benjamins, Jan W. Engmann, Jorgen Kember, Rachel L. Slieker, Roderick C. Lo, Ken Sin Zilhao, Nuno R. Phuong Le and Kleber, Marcus E. Delgado, Graciela E. Huo, Shaofeng Ikeda, Daisuke D. Iha, Hiroyuki Yang, Jian Liu, Jun Leonard, Hampton L. Marten, Jonathan Schmidt, Borge Arendt, Marina and Smyth, Laura J. Canadas-Garre, Marisa Wang, Chaolong and Nakatochi, Masahiro Wong, Andrew Hutri-Kahonen, Nina Sim, Xueling Xia, Rui Huerta-Chagoya, Alicia Fernandez-Lopez, Juan Carlos Lyssenko, Valeriya Ahmed, Meraj Jackson, Anne U. and Irvin, Marguerite R. Oldmeadow, Christopher Kim, Han-Na and Ryu, Seungho Timmers, Paul R. H. J. Arbeeva, Liubov Dorajoo, Rajkumar Lange, Leslie A. Chai, Xiaoran Prasad, Gauri and Lores-Motta, Laura Pauper, Marc Long, Jirong Li, Xiaohui and Theusch, Elizabeth Takeuchi, Fumihiko Spracklen, Cassandra N. and Loukola, Anu Bollepalli, Sailalitha Warner, Sophie C. and Wang, Ya Xing Wei, Wen B. Nutile, Teresa Ruggiero, Daniela and Sung, Yun Ju Hung, Yi-Jen Chen, Shufeng Liu, Fangchao and Yang, Jingyun Kentistou, Katherine A. Gorski, Mathias and Brumat, Marco Meidtner, Karina Bielak, Lawrence F. Smith, Jennifer A. Hebbar, Prashantha Farmaki, Aliki-Eleni Hofer, Edith Lin, Maoxuan Xue, Chao Zhang, Jifeng Concas, Maria Pina Vaccargiu, Simona van der Most, Peter J. Pitkanen, Niina Cade, Brian E. Lee, Jiwon van Der Laan, Sander W. and Chitrala, Kumaraswamy Naidu Weiss, Stefan Zimmermann, Martina E. and Lee, Jong Young Choi, Hyeok Sun Nethander, Maria and Freitag-Wolf, Sandra Southam, Lorraine Rayner, Nigel W. and Wang, Carol A. Lin, Shih-Yi Wang, Jun-Sing Couture, Christian Lyytikainen, Leo-Pekka Nikus, Kjell and Cuellar-Partida, Gabriel Vestergaard, Henrik Hildalgo, Bertha and Giannakopoulou, Olga Cai, Qiuyin Obura, Morgan O. van Setten, Jessica Li, Xiaoyin Schwander, Karen Terzikhan, Natalie Shin, Jae Hun Jackson, Rebecca D. Reiner, Alexander P. Martin, Lisa Warsinger Chen, Zhengming Li, Liming and Highland, Heather M. Young, Kristin L. Kawaguchi, Takahisa and Thiery, Joachim Bis, Joshua C. Nadkarni, Girish N. Launer, Lenore J. Li, Huaixing Nalls, Mike A. Raitakari, Olli T. and Ichihara, Sahoko Wild, Sarah H. Nelson, Christopher P. and Campbell, Harry Jager, Susanne Nabika, Toru Al-Mulla, Fahd and Niinikoski, Harri Braund, Peter S. Kolcic, Ivana Kovacs, Peter Giardoglou, Tota Katsuya, Tomohiro Bhatti, Fatima and de Kleijn, Dominique de Borst, Gert J. Kim, Eung Kweon and Adams, Hieab H. H. Ikram, M. Arfan Zhu, Xiaofeng Asselbergs, Folkert W. Kraaijeveld, Adriaan O. Beulens, Joline W. J. and Shu, Xiao-Ou Rallidis, Loukianos S. Pedersen, Oluf Hansen, Torben Mitchell, Paul Hewitt, Alex W. Kahonen, Mika and Perusse, Louis Bouchard, Claude Tonjes, Anke Chen, Yii-Der Ida Pennell, Craig E. Mori, Trevor A. Lieb, Wolfgang and Franke, Andre Ohlsson, Claes Mellstrom, Dan Cho, Yoon Shin and Lee, Hyejin Yuan, Jian-Min Koh, Woon-Puay Rhee, Sang Youl Woo, Jeong-Taek Heid, Iris M. Stark, Klaus J. and Volzke, Henry Homuth, Georg Evans, Michele K. Zonderman, Alan B. Polasek, Ozren Pasterkamp, Gerard Hoefer, Imo E. and Redline, Susan Pahkala, Katja Oldehinkel, Albertine J. and Snieder, Harold Biino, Ginevra Schmidt, Reinhold Schmidt, Helena Chen, Y. Eugene Bandinelli, Stefania Dedoussis, George Thanaraj, Thangavel Alphonse Kardia, Sharon L. R. and Kato, Norihiro Schulze, Matthias B. Girotto, Giorgia Jung, Bettina Boger, Carsten A. Joshi, Peter K. Bennett, David A. and De Jager, Philip L. Lu, Xiangfeng Mamakou, Vasiliki and Brown, Morris Caulfield, Mark J. Munroe, Patricia B. Guo, Xiuqing Ciullo, Marina Jonas, Jost B. Samani, Nilesh J. and Kaprio, Jaakko Pajukanta, Paivi Adair, Linda S. Bechayda, Sonny Augustin de Silva, H. Janaka Wickremasinghe, Ananda R. and Krauss, Ronald M. Wu, Jer-Yuarn Zheng, Wei den Hollander, I, Anneke Bharadwaj, Dwaipayan Correa, Adolfo Wilson, James G. and Lind, Lars Heng, Chew-Kiat Nelson, Amanda E. Golightly, Yvonne M. Wilson, James F. Penninx, Brenda Kim, Hyung-Lae and Attia, John Scott, Rodney J. Rao, D. C. Arnett, Donna K. and Walker, Mark Koistinen, Heikki A. Chandak, Giriraj R. and Yajnik, Chittaranjan S. Mercader, Josep M. Tusie-Luna, Teresa and Aguilar-Salinas, Carlos A. Villalpando, Clicerio Gonzalez and Orozco, Lorena Fornage, Myriam Tai, E. Shyong van Dam, Rob M. Lehtimaki, Terho Chaturvedi, Nish Yokota, Mitsuhiro and Liu, Jianjun Reilly, Dermot F. McKnight, Amy Jayne Kee, Frank Jockel, Karl-Heinz McCarthy, I, Mark Palmer, Colin N. A. Vitart, Veronique Hayward, Caroline Simonsick, Eleanor and van Duijn, Cornelia M. Lu, Fan Qu, Jia Hishigaki, Haretsugu Lin, Xu Marz, Winfried Parra, Esteban J. Cruz, Miguel Gudnason, Vilmundur Tardif, Jean-Claude Lettre, Guillaume `t Hart, Leen M. Elders, Petra J. M. Damrauer, Scott M. Kumari, Meena Kivimaki, Mika van der Harst, Pim and Spector, Tim D. Loos, Ruth J. F. Province, Michael A. Psaty, Bruce M. Brandslund, Ivan Pramstaller, Peter P. Christensen, Kaare Ripatti, Samuli Widen, Elisabeth Hakonarson, Hakon and Grant, Struan F. A. Kiemeney, Lambertus A. L. M. de Graaf, Jacqueline Loeffler, Markus Kronenberg, Florian Gu, Dongfeng and Erdmann, Jeanette Schunkert, Heribert Franks, Paul W. and Linneberg, Allan Jukema, J. Wouter Khera, V, Amit Mannikko, Minna Jarvelin, Marjo-Riitta Kutalik, Zoltan Cucca, Francesco Mook-Kanamori, Dennis O. van Dijk, Ko Willems and Watkins, Hugh Strachan, David P. Grarup, Niels Sever, Peter and Poulter, Neil Rotter, I, Jerome Dantoft, Thomas M. and Karpe, Fredrik Neville, Matt J. Timpson, Nicholas J. Cheng, Ching-Yu Wong, Tien-Yin Khor, Chiea Chuen Sabanayagam, Charumathi Peters, Annette Gieger, Christian Hattersley, Andrew T. Pedersen, Nancy L. Magnusson, Patrik K. E. and Boomsma, I, Dorret de Geus, Eco J. C. Cupples, L. Adrienne and van Meurs, Joyce B. J. Ghanbari, Mohsen Rsen, Penny Gordon-La and Huang, Wei Kim, Young Jin Tabara, Yasuharu Wareham, Nicholas J. Langenberg, Claudia Zeggini, Eleftheria and Kuusisto, Johanna Laakso, Markku Ingelsson, Erik Abecasis, Goncalo Chambers, John C. Kooner, Jaspal S. de Vries, Paul S. Morrison, Alanna C. North, Kari E. Daviglus, Martha and Kraft, Peter Martin, Nicholas G. Whitfield, John B. Abbas, Shahid Saleheen, Danish Walters, Robin G. Holmes, V, Michael and Black, Corri Smith, Blair H. Justice, Anne E. Baras, Aris Buring, Julie E. Ridker, Paul M. Chasman, I, Daniel and Kooperberg, Charles Wei, Wei-Qi Jarvik, Gail P. Namjou, Bahram Hayes, M. Geoffrey Ritchie, Marylyn D. Jousilahti, Pekka Salomaa, Veikko Hveem, Kristian Asvold, Bjorn Olav and Kubo, Michiaki Kamatani, Yoichiro Okada, Yukinori Murakami, Yoshinori Thorsteinsdottir, Unnur Stefansson, Kari Ho, Yuk-Lam Lynch, Julie A. Rader, Daniel J. Tsao, Philip S. and Chang, Kyong-Mi Cho, Kelly O'Donnell, Christopher J. and Gaziano, John M. Wilson, Peter Rotimi, Charles N. and Hazelhurst, Scott Ramsay, Michele Trembath, Richard C. van Heel, David A. Tamiya, Gen Yamamoto, Masayuki Kim, Bong-Jo and Mohlke, Karen L. Frayling, Timothy M. Hirschhorn, Joel N. and Kathiresan, Sekar Boehnke, Michael Natarajan, Pradeep and Peloso, Gina M. Brown, Christopher D. Morris, Andrew P. and Assimes, Themistocles L. Deloukas, Panos Sun, V, Yan Willer, Cristen J.
- Abstract
Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use(1). Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels(2), heart disease remains the leading cause of death worldwide(3). Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS(4-23) have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns(24). Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine(25), we anticipate that increased diversity of participants will lead to more accurate and equitable(26) application of polygenic scores in clinical practice.
- Published
- 2021