학술논문
The power of genetic diversity in genome-wide association studies of lipids
Document Type
Original Paper
Author
Graham, Sarah E.; Clarke, Shoa L.; Wu, Kuan-Han H.; Kanoni, Stavroula; Zajac, Greg J. M.; Ramdas, Shweta; Surakka, Ida; Ntalla, Ioanna; Vedantam, Sailaja; Winkler, Thomas W.; Locke, Adam E.; Marouli, Eirini; Hwang, Mi Yeong; Han, Sohee; Narita, Akira; Choudhury, Ananyo; Bentley, Amy R.; Ekoru, Kenneth; Verma, Anurag; Trivedi, Bhavi; Martin, Hilary C.; Hunt, Karen A.; Hui, Qin; Klarin, Derek; Zhu, Xiang; Thorleifsson, Gudmar; Helgadottir, Anna; Gudbjartsson, Daniel F.; Holm, Hilma; Olafsson, Isleifur; Akiyama, Masato; Sakaue, Saori; Terao, Chikashi; Kanai, Masahiro; Zhou, Wei; Brumpton, Ben M.; Rasheed, Humaira; Ruotsalainen, Sanni E.; Havulinna, Aki S.; Veturi, Yogasudha; Feng, QiPing; Rosenthal, Elisabeth A.; Lingren, Todd; Pacheco, Jennifer Allen; Pendergrass, Sarah A.; Haessler, Jeffrey; Giulianini, Franco; Bradford, Yuki; Miller, Jason E.; Campbell, Archie; Lin, Kuang; Millwood, Iona Y.; Hindy, George; Rasheed, Asif; Faul, Jessica D.; Zhao, Wei; Weir, David R.; Turman, Constance; Huang, Hongyan; Graff, Mariaelisa; Mahajan, Anubha; Brown, Michael R.; Zhang, Weihua; Yu, Ketian; Schmidt, Ellen M.; Pandit, Anita; Gustafsson, Stefan; Yin, Xianyong; Luan, Jian’an; Zhao, Jing-Hua; Matsuda, Fumihiko; Jang, Hye-Mi; Yoon, Kyungheon; Medina-Gomez, Carolina; Pitsillides, Achilleas; Hottenga, Jouke Jan; Willemsen, Gonneke; Wood, Andrew R.; Ji, Yingji; Gao, Zishan; Haworth, Simon; Mitchell, Ruth E.; Chai, Jin Fang; Aadahl, Mette; Yao, Jie; Manichaikul, Ani; Warren, Helen R.; Ramirez, Julia; Bork-Jensen, Jette; Kårhus, Line L.; Goel, Anuj; Sabater-Lleal, Maria; Noordam, Raymond; Sidore, Carlo; Fiorillo, Edoardo; McDaid, Aaron F.; Marques-Vidal, Pedro; Wielscher, Matthias; Trompet, Stella; Sattar, Naveed; Møllehave, Line T.; Thuesen, Betina H.; Munz, Matthias; Zeng, Lingyao; Huang, Jianfeng; Yang, Bin; Poveda, Alaitz; Kurbasic, Azra; Lamina, Claudia; Forer, Lukas; Scholz, Markus; Galesloot, Tessel E.; Bradfield, Jonathan P.; Daw, E. Warwick; Zmuda, Joseph M.; Mitchell, Jonathan S.; Fuchsberger, Christian; Christensen, Henry; Brody, Jennifer A.; Feitosa, Mary F.; Wojczynski, Mary K.; Preuss, Michael; Mangino, Massimo; Christofidou, Paraskevi; Verweij, Niek; Benjamins, Jan W.; Engmann, Jorgen; Kember, Rachel L.; Slieker, Roderick C.; Lo, Ken Sin; Zilhao, Nuno R.; Le, Phuong; Kleber, Marcus E.; Delgado, Graciela E.; Huo, Shaofeng; Ikeda, Daisuke D.; Iha, Hiroyuki; Yang, Jian; Liu, Jun; Leonard, Hampton L.; Marten, Jonathan; Schmidt, Börge; Arendt, Marina; Smyth, Laura J.; Cañadas-Garre, Marisa; Wang, Chaolong; Nakatochi, Masahiro; Wong, Andrew; Hutri-Kähönen, Nina; Sim, Xueling; Xia, Rui; Huerta-Chagoya, Alicia; Fernandez-Lopez, Juan Carlos; Lyssenko, Valeriya; Ahmed, Meraj; Jackson, Anne U.; Yousri, Noha A.; Irvin, Marguerite R.; Oldmeadow, Christopher; Kim, Han-Na; Ryu, Seungho; Timmers, Paul R. H. J.; Arbeeva, Liubov; Dorajoo, Rajkumar; Lange, Leslie A.; Chai, Xiaoran; Prasad, Gauri; Lorés-Motta, Laura; Pauper, Marc; Long, Jirong; Li, Xiaohui; Theusch, Elizabeth; Takeuchi, Fumihiko; Spracklen, Cassandra N.; Loukola, Anu; Bollepalli, Sailalitha; Warner, Sophie C.; Wang, Ya Xing; Wei, Wen B.; Nutile, Teresa; Ruggiero, Daniela; Sung, Yun Ju; Hung, Yi-Jen; Chen, Shufeng; Liu, Fangchao; Yang, Jingyun; Kentistou, Katherine A.; Gorski, Mathias; 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.; Pitkänen, Niina; Cade, Brian E.; Lee, Jiwon; van der Laan, Sander W.; Chitrala, Kumaraswamy Naidu; Weiss, Stefan; Zimmermann, Martina E.; Lee, Jong Young; Choi, Hyeok Sun; Nethander, Maria; Freitag-Wolf, Sandra; Southam, Lorraine; Rayner, Nigel W.; Wang, Carol A.; Lin, Shih-Yi; Wang, Jun-Sing; Couture, Christian; Lyytikäinen, Leo-Pekka; Nikus, Kjell; Cuellar-Partida, Gabriel; Vestergaard, Henrik; Hildalgo, Bertha; 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; Highland, Heather M.; Young, Kristin L.; Kawaguchi, Takahisa; Thiery, Joachim; Bis, Joshua C.; Nadkarni, Girish N.; Launer, Lenore J.; Li, Huaixing; Nalls, Mike A.; Raitakari, Olli T.; Ichihara, Sahoko; Wild, Sarah H.; Nelson, Christopher P.; Campbell, Harry; Jäger, Susanne; Nabika, Toru; Al-Mulla, Fahd; Niinikoski, Harri; Braund, Peter S.; Kolcic, Ivana; Kovacs, Peter; Giardoglou, Tota; Katsuya, Tomohiro; Bhatti, Konain Fatima; de Kleijn, Dominique; de Borst, Gert J.; Kim, Eung Kweon; Adams, Hieab H. H.; Ikram, M. Arfan; Zhu, Xiaofeng; Asselbergs, Folkert W.; Kraaijeveld, Adriaan O.; Beulens, Joline W. J.; Shu, Xiao-Ou; Rallidis, Loukianos S.; Pedersen, Oluf; Hansen, Torben; Mitchell, Paul; Hewitt, Alex W.; Kähönen, Mika; Pérusse, Louis; Bouchard, Claude; Tönjes, Anke; Chen, Yii-Der Ida; Pennell, Craig E.; Mori, Trevor A.; Lieb, Wolfgang; Franke, Andre; Ohlsson, Claes; Mellström, Dan; Cho, Yoon Shin; Lee, Hyejin; Yuan, Jian-Min; Koh, Woon-Puay; Rhee, Sang Youl; Woo, Jeong-Taek; Heid, Iris M.; Stark, Klaus J.; Völzke, Henry; Homuth, Georg; Evans, Michele K.; Zonderman, Alan B.; Polasek, Ozren; Pasterkamp, Gerard; Hoefer, Imo E.; Redline, Susan; Pahkala, Katja; Oldehinkel, Albertine J.; Snieder, Harold; Biino, Ginevra; Schmidt, Reinhold; Schmidt, Helena; Chen, Y. Eugene; Bandinelli, Stefania; Dedoussis, George; Thanaraj, Thangavel Alphonse; Kardia, Sharon L. R.; Kato, Norihiro; Schulze, Matthias B.; Girotto, Giorgia; Jung, Bettina; Böger, Carsten A.; Joshi, Peter K.; Bennett, David A.; De Jager, Philip L.; Lu, Xiangfeng; Mamakou, Vasiliki; Brown, Morris; Caulfield, Mark J.; Munroe, Patricia B.; Guo, Xiuqing; Ciullo, Marina; Jonas, Jost B.; Samani, Nilesh J.; Kaprio, Jaakko; Pajukanta, Päivi; Adair, Linda S.; Bechayda, Sonny Augustin; de Silva, H. Janaka; Wickremasinghe, Ananda R.; Krauss, Ronald M.; Wu, Jer-Yuarn; Zheng, Wei; den Hollander, Anneke I.; Bharadwaj, Dwaipayan; Correa, Adolfo; Wilson, James G.; Lind, Lars; Heng, Chew-Kiat; Nelson, Amanda E.; Golightly, Yvonne M.; Wilson, James F.; Penninx, Brenda; Kim, Hyung-Lae; Attia, John; Scott, Rodney J.; Rao, D. C.; Arnett, Donna K.; Hunt, Steven C.; Walker, Mark; Koistinen, Heikki A.; Chandak, Giriraj R.; Yajnik, Chittaranjan S.; Mercader, Josep M.; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Villalpando, Clicerio Gonzalez; Orozco, Lorena; Fornage, Myriam; Tai, E. Shyong; van Dam, Rob M.; Lehtimäki, Terho; Chaturvedi, Nish; Yokota, Mitsuhiro; Liu, Jianjun; Reilly, Dermot F.; McKnight, Amy Jayne; Kee, Frank; Jöckel, Karl-Heinz; McCarthy, Mark I.; Palmer, Colin N. A.; Vitart, Veronique; Hayward, Caroline; Simonsick, Eleanor; van Duijn, Cornelia M.; Lu, Fan; Qu, Jia; Hishigaki, Haretsugu; Lin, Xu; März, 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; Spector, Tim D.; Loos, Ruth J. F.; Province, Michael A.; Psaty, Bruce M.; Brandslund, Ivan; Pramstaller, Peter P.; Christensen, Kaare; Ripatti, Samuli; Widén, Elisabeth; Hakonarson, Hakon; Grant, Struan F. A.; Kiemeney, Lambertus A. L. M.; de Graaf, Jacqueline; Loeffler, Markus; Kronenberg, Florian; Gu, Dongfeng; Erdmann, Jeanette; Schunkert, Heribert; Franks, Paul W.; Linneberg, Allan; Jukema, J. Wouter; Khera, Amit V.; Männikkö, Minna; Jarvelin, Marjo-Riitta; Kutalik, Zoltan; Cucca, Francesco; Mook-Kanamori, Dennis O.; van Dijk, Ko Willems; Watkins, Hugh; Strachan, David P.; Grarup, Niels; Sever, Peter; Poulter, Neil; Rotter, Jerome I.; Dantoft, Thomas M.; 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.; Boomsma, Dorret I.; de Geus, Eco J. C.; Cupples, L. Adrienne; van Meurs, Joyce B. J.; Ghanbari, Mohsen; Gordon-Larsen, Penny; Huang, Wei; Kim, Young Jin; Tabara, Yasuharu; Wareham, Nicholas J.; Langenberg, Claudia; Zeggini, Eleftheria; 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; Kraft, Peter; Martin, Nicholas G.; Whitfield, John B.; Abbas, Shahid; Saleheen, Danish; Walters, Robin G.; Holmes, Michael V.; Black, Corri; Smith, Blair H.; Justice, Anne E.; Baras, Aris; Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.; Kooperberg, Charles; Wei, Wei-Qi; Jarvik, Gail P.; Namjou, Bahram; Hayes, M. Geoffrey; Ritchie, Marylyn D.; Jousilahti, Pekka; Salomaa, Veikko; Hveem, Kristian; Åsvold, Bjørn Olav; Kubo, Michiaki; Kamatani, Yoichiro; Okada, Yukinori; Murakami, Yoshinori; Thorsteinsdottir, Unnur; Stefansson, Kari; Ho, Yuk-Lam; Lynch, Julie A.; Rader, Daniel J.; Tsao, Philip S.; Chang, Kyong-Mi; Cho, Kelly; O’Donnell, Christopher J.; Gaziano, John M.; Wilson, Peter; Rotimi, Charles N.; Hazelhurst, Scott; Ramsay, Michèle; Trembath, Richard C.; van Heel, David A.; Tamiya, Gen; Yamamoto, Masayuki; Kim, Bong-Jo; Mohlke, Karen L.; Frayling, Timothy M.; Hirschhorn, Joel N.; Kathiresan, Sekar; Boehnke, Michael; Natarajan, Pradeep; Peloso, Gina M.; Brown, Christopher D.; Morris, Andrew P.; Assimes, Themistocles L.; Deloukas, Panos; Sun, Yan V.; Willer, Cristen J.
Source
Nature: International weekly journal of science. 600(7890):675-679
Subject
Language
English
ISSN
0028-0836
1476-4687
1476-4687
Abstract
Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2 , heart disease remains the leading cause of death worldwide3 . 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 GWAS4–23 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 patterns24 . 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 medicine25 , we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.
A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.
A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.