The power of genetic diversity in genome-wide association studies of lipids
Autoren
Sarah Graham, Shoa Clarke, Kuan-Han Wu, Stavroula Kanoni, Greg Zajac, Shweta Ramdas, Ida Surakka, Ioanna Ntalla, Sailaja Vedantam, Thomas Winkler, Adam Locke, Eirini Marouli, Mi Hwang, Sohee Han, Akira Narita, Ananyo Choudhury, Amy Bentley, Kenneth Ekoru, Anurag Verma, Bhavi Trivedi, Hilary Martin, Karen Hunt, Qin Hui, Derek Klarin, Xiang Zhu, Gudmar Thorleifsson, Anna Helgadottir, Daniel Gudbjartsson, Hilma Holm, Isleifur Olafsson, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben Brumpton, Humaira Rasheed, Sanni Ruotsalainen, Aki Havulinna, Yogasudha Veturi, QiPing Feng, Elisabeth Rosenthal, Todd Lingren, Jennifer Pacheco, Sarah Pendergrass, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason Miller, Archie Campbell, Kuang Lin, Iona Millwood, George Hindy, Asif Rasheed, Jessica Faul, Wei Zhao, David Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Anubha Mahajan, Michael Brown, Weihua Zhang, Ketian Yu, Ellen 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 Hottenga, Gonneke Willemsen, Andrew Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth Mitchell, Jin Chai, Mette Aadahl, Jie Yao, Ani Manichaikul, Helen Warren, Julia Ramirez, Jette Bork-Jensen, Line Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Carlo Sidore, Edoardo Fiorillo, Aaron McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line Møllehave, Betina Thuesen, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel Galesloot, Jonathan Bradfield, E. Daw, Joseph Zmuda, Jonathan Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer Brody, Mary Feitosa, Mary Wojczynski, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan Benjamins, Jorgen Engmann, Rachel Kember, Roderick Slieker, Ken Lo, Nuno Zilhao, Phuong Le, Marcus Kleber, Graciela Delgado, Shaofeng Huo, Daisuke Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Hampton Leonard, Jonathan Marten, Börge Schmidt, Marina Arendt, Laura Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Fernandez-Lopez, Valeriya Lyssenko, Meraj Ahmed, Anne Jackson, Marguerite Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Timmers, Paul R H J, Liubov Arbeeva, Rajkumar Dorajoo, Leslie Lange, Xiaoran Chai, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie Warner, Ya Wang, Wen Wei, Teresa Nutile, Daniela Ruggiero, Yun Sung, Yi-Jen Hung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine Kentistou, Mathias Gorski, Marco Brumat, Karina Meidtner, Lawrence Bielak, Jennifer Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Chao Xue, Jifeng Zhang, Maria Concas, Simona Vaccargiu, van der Most, Peter J, Niina Pitkänen, Brian Cade, Jiwon Lee, van der Laan, Sander W, Kumaraswamy Chitrala, Stefan Weiss, Martina Zimmermann, Jong Lee, Hyeok Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel Rayner, Carol Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hildalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan Obura, Jessica van Setten, Xiaoyin Li, Karen Schwander, Natalie Terzikhan, Jae Shin, Rebecca Jackson, Alexander Reiner, Lisa Martin, Zhengming Chen, Liming Li, Heather Highland, Kristin Young, Takahisa Kawaguchi, Joachim Thiery, Joshua Bis, Girish Nadkarni, Lenore Launer, Huaixing Li, Mike Nalls, Olli Raitakari, Sahoko Ichihara, Sarah Wild, Christopher Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Konain Bhatti, Dominique Kleijn, Gert Borst, Eung Kim, Hieab Adams, M. Ikram, Xiaofeng Zhu, Folkert Asselbergs, Adriaan Kraaijeveld, Joline Beulens, Xiao-Ou Shu, Loukianos Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Chen, Craig Pennell, Trevor Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Rhee, Jeong-Taek Woo, Iris Heid, Klaus Stark, Henry Völzke, Georg Homuth, Michele Evans, Alan Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo Hoefer, Susan Redline, Katja Pahkala, Albertine Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Y. Chen, Stefania Bandinelli, George Dedoussis, Thangavel Thanaraj, Sharon Kardia, Norihiro Kato, Matthias Schulze, Giorgia Girotto, Bettina Jung, Carsten Böger, Peter Joshi, David Bennett, Philip Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark Caulfield, Patricia Munroe, Xiuqing Guo, Marina Ciullo, Jost Jonas, Nilesh Samani, Jaakko Kaprio, Päivi Pajukanta, Linda Adair, Sonny Bechayda, H. Silva, Ananda Wickremasinghe, Ronald Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James Wilson, Lars Lind, Chew-Kiat Heng, Amanda Nelson, Yvonne Golightly, James Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney Scott, D. Rao, Donna Arnett, Mark Walker, Heikki Koistinen, Giriraj Chandak, Chittaranjan Yajnik, Josep Mercader, Teresa Tusié-Luna, Carlos Aguilar-Salinas, Clicerio Villalpando, Lorena Orozco, Myriam Fornage, E. Tai, Rob van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot Reilly, Amy McKnight, Frank Kee, Karl-Heinz Jöckel, Mark McCarthy, Colin Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia van Duijn, Fan Lu, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Esteban Parra, Miguel Cruz, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen Hart, Petra Elders, Scott Damrauer, Meena Kumari, Mika Kivimaki, van der Harst, Pim, Tim Spector, Ruth Loos, Michael Province, Bruce Psaty, Ivan Brandslund, Peter Pramstaller, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan Grant, Kiemeney, Lambertus A L M, Jacqueline Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul Franks, Allan Linneberg, J. Jukema, Amit Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Francesco Cucca, Dennis Mook-Kanamori, Ko van Dijk, Hugh Watkins, David Strachan, Niels Grarup, Peter Sever, Neil Poulter, Jerome Rotter, Thomas Dantoft, Fredrik Karpe, Matt Neville, Nicholas Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Khor, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew Hattersley, Nancy Pedersen, Patrik Magnusson, Dorret Boomsma, de Geus, Eco J C, L. Cupples, van Meurs, Joyce B J, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Kim, Yasuharu Tabara, Nicholas Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John Chambers, Jaspal Kooner, Paul Vries, Alanna Morrison, Kari North, Martha Daviglus, Peter Kraft, Nicholas Martin, John Whitfield, Shahid Abbas, Danish Saleheen, Robin Walters, Michael Holmes, Corri Black, Blair Smith, Anne Justice, Aris Baras, Julie Buring, Paul Ridker, Daniel Chasman, Charles Kooperberg, Wei-Qi Wei, Gail Jarvik, Bahram Namjou, M. Hayes, Marylyn Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Unnur Thorsteinsdottir, Kari Stefansson, Yuk-Lam Ho, Julie Lynch, Daniel Rader, Philip Tsao, Kyong-Mi Chang, Kelly Cho, Christopher O'Donnell, John Gaziano, Peter Wilson, Charles Rotimi, Scott Hazelhurst, Michèle Ramsay, Richard Trembath, David van Heel, Gen Tamiya, Masayuki Yamamoto, Bong-Jo Kim, Karen Mohlke, Timothy Frayling, Joel Hirschhorn, Sekar Kathiresan, Michael Boehnke, Pradeep Natarajan, Gina Peloso, Christopher Brown, Andrew Morris, Themistocles Assimes, Panos Deloukas, Yan Sun, Cristen Willer
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.