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

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    Date
    2021-12-23
    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, 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
    ...show more authors ...show less authors
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    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.
    URI
    https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85121605114&origin=inward
    DOI/handle
    http://dx.doi.org/10.1038/s41586-021-04064-3
    http://hdl.handle.net/10576/46845
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    • Medicine Research [‎1819‎ items ]

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