The Power of Genetic Diversity in Genome-Wide Association Studies of Lipids

Citation

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., et al. (2021). The Power of Genetic Diversity in Genome-Wide Association Studies of Lipids. Nature, 600(7890), 675-679. PMCID: PMC8730582

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.

URL

http://dx.doi.org/10.1038/s41586-021-04064-3

Reference Type

Journal Article

Year Published

2021

Journal Title

Nature

Author(s)

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 A.
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 J.
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 H.
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
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.
Irvin, Marguerite Ryan
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 N.
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, J. H.
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 K.
Adams, Hieab H. H.
Ikram, M. A.
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 S.
Pahkala, Katja
Oldehinkel, Albertine J.
Snieder, Harold
Biino, Ginevra
Schmidt, Reinhold
Schmidt, Helena
Chen, Y. Eugene
Bandinelli, Stefania
Dedoussis, George
Thanaraj, Thangavel A.
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 J.
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 A.
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 W. J. H. W.
Kim, Hyung-Lae
Attia, John R.
Scott, Rodney J.
Rao, D. C.
Arnett, Donna K.
Walker, Mark
Koistinen, Heikki A.
Chandak, Giriraj R.
Yajnik, Chittaranjan S.
Mercader, Josep M.
Tusié-Luna, Teresa
Aguilar-Salinas, Carlos A.
Villalpando, C. G.
Orozco, Lorena
Fornage, Myriam
Tai, E. S.
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
Cruz, Miguel
Gudnason, Vilmundur G.
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.
de Graaf, Jacqueline
Loeffler, Markus
Kronenberg, Florian
Gu, Dongfeng
Erdmann, Jeanette
Schunkert, Heribert
Franks, Paul W.
Linneberg, Allan
Jukema, J. W.
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
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 R.
Chambers, John C.
Kooner, Jaspal S.
de Vries, Paul S.
Morrison, Alanna C.
North, Kari E.
Daviglus, Martha L.
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. G.
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.

Article Type

Regular

PMCID

PMC8730582

Data Set/Study

UK Biobank Study

Continent/Country

United Kingdom

ORCiD

Adair - 0000-0002-3670-8073
Gordon-Larsen - 0000-0001-5322-4188