The power of genetic diversity in genome-wide association studies of lipids

Sarah E. Graham, Shoa L. Clarke, Kuan-Han H. Wu, Stavroula Kanoni, Greg J. M. Zajac, Shweta Ramdas, Ida Surakka, Ioanna Ntalla, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Mi Yeong Hwang, Sohee Han, Akira Narita, Ananyo Choudhury, Amy R. Bentley, Kenneth Ekoru, Anurag Verma, Bhavi TrivediHilary C. Martin, Karen A. Hunt, Qin Hui, Derek Klarin, Xiang Zhu, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Sanni E. Ruotsalainen, Aki S. Havulinna, Yogasudha Veturi, QiPing Feng, Elisabeth A. Rosenthal, Todd Lingren, Jennifer Allen Pacheco, Sarah A. Pendergrass, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, George Hindy, Asif Rasheed, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, 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, Gonneke Willemsen, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Jie Yao, Ani Manichaikul, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Karhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Carlo Sidore, Edoardo Fiorillo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Mollehave, Betina H. Thuesen, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, E. Warwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Mary F. Feitosa, Mary K. Wojczynski, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Rachel L. Kember, 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, Hampton L. Leonard, Jonathan Marten, Borge Schmidt, Marina Arendt, Laura J. Smyth, Marisa Canadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kahonen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Meraj Ahmed, Anne U. Jackson, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Xiaoran Chai, Gauri Prasad, Laura Lores-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, Yi-Jen Hung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Mathias Gorski, Marco Brumat, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Chao Xue, Jifeng Zhang, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkanen, Brian E. Cade, Jiwon Lee, Sander W. van Der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Martina E. Zimmermann, Jong Young Lee, 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 Lyytikainen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hildalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Karen Schwander, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Heather M. Highland, Kristin L. Young, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Girish N. Nadkarni, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jager, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Fatima Bhatti, 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 Kahonen, Louis Perusse, Claude Bouchard, Anke Tonjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellstrom, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Henry Volzke, 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, Y. Eugene Chen, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Bettina Jung, Carsten A. Boger, 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, Paivi Pajukanta, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke den 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, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Chittaranjan S. Yajnik, Josep M. Mercader, Teresa Tusie-Luna, Carlos A. Aguilar-Salinas, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, E. Shyong Tai, Rob M. van Dam, Terho Lehtimaki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jockel, Mark McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Fan Lu, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried Marz, Esteban J. Parra, Miguel Cruz, 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, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Kaare Christensen, Samuli Ripatti, Elisabeth Widen, 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 Khera, Minna Mannikko, Marjo-Riitta Jarvelin, Zoltan Kutalik, Francesco Cucca, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Jerome Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret Boomsma, Eco J. C. de Geus, L. Adrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-La Rsen, 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, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael Holmes, Corri Black, Blair H. Smith, Anne E. Justice, Aris Baras, Julie E. Buring, Paul M. Ridker, Daniel Chasman, Charles Kooperberg, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjorn Olav Asvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Unnur Thorsteinsdottir, Kari Stefansson, 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 Wilson, Charles N. Rotimi, Scott Hazelhurst, Michele Ramsay, Richard C. Trembath, David A. van Heel, Gen Tamiya, Masayuki Yamamoto, Bong-Jo Kim, Karen L. Mohlke, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Michael Boehnke, Pradeep Natarajan, Gina M. Peloso, Christopher D. Brown, Andrew P. Morris, Themistocles L. Assimes, Panos Deloukas, Yan Sun, Cristen J. Willer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)675–679
Number of pages25
JournalNature
Volume600
Early online date9 Dec 2021
DOIs
Publication statusPublished - 23 Dec 2021

Keywords

  • LOW-FREQUENCY
  • LOCI
  • METAANALYSIS
  • CHOLESTEROL
  • ANCESTRY
  • POLYMORPHISMS
  • DISCOVERY
  • VARIANTS
  • RISK
  • INDIVIDUALS

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