The power of genetic diversity in genome-wide association studies of lipids
Date
2021-12-23Author
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, Qi Ping
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
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Metadata
Show full item recordAbstract
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.
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