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

Graham, SE, Clarke, SL, Wu, KHH, Kanoni, S, Zajac, GJM, Ramdas, S, Surakka, I, Ntalla, I, Vedantam, S, Winkler, TW, Locke, AE, Marouli, E, Hwang, MY, Han, S, Narita, A, Choudhury, A, Bentley, AR, Ekoru, K, Verma, A, Trivedi, B, Martin, HC, Hunt, KA, Hui, Q, Klarin, D, Zhu, X, Thorleifsson, G, Helgadottir, A, Gudbjartsson, DF, Holm, H, Olafsson, I, Akiyama, M, Sakaue, S, Terao, C, Kanai, M, Zhou, W, Brumpton, BM, Rasheed, H, Ruotsalainen, SE, Havulinna, AS, Veturi, Y, Feng, QP, Rosenthal, EA, Lingren, T, Pacheco, JA, Pendergrass, SA, Haessler, J, Giulianini, F, Bradford, Y, Miller, JE, Campbell, A, Lin, K, Millwood, IY, Hindy, G, Rasheed, A, Faul, JD, Zhao, W, Weir, DR, Turman, C, Huang, H, Graff, M, Mahajan, A, Brown, MR, Zhang, W, Yu, K, Schmidt, EM, Pandit, A, Gustafsson, S, Yin, S, Luan, J, Zhao, JH, Matsuda, F, Jang, HM, Yoon, K, Medina-Gomez, C, Pitsillides, A, Hottenga, JJ, Willemsen, G, Wood, AR, Ji, Y, Gao, Z, Haworth, S, Mitchell, RE, Chai, JF, Aadahl, M, Yao, J, Manichaikul, A, Warren, HR, Ramirez, J, Bork-Jensen, J, Karhus, LL, Goel, A, Sabater-Lleal, M, Noordam, R, Sidore, C, Fiorillo, E, McDaid, AF, Marques-Vidal, P, Wielscher, M, Trompet, S and Hewitt, AW ORCID: 0000-0002-5123-5999 2021 , 'The power of genetic diversity in genome wide association studies of lipids' , Nature, vol. 600, no. 7890 , pp. 675-679 , doi: 10.1038/s41586-021-04064-3.

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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.

Item Type: Article
Authors/Creators:Graham, SE and Clarke, SL and Wu, KHH and Kanoni, S and Zajac, GJM and Ramdas, S and Surakka, I and Ntalla, I and Vedantam, S and Winkler, TW and Locke, AE and Marouli, E and Hwang, MY and Han, S and Narita, A and Choudhury, A and Bentley, AR and Ekoru, K and Verma, A and Trivedi, B and Martin, HC and Hunt, KA and Hui, Q and Klarin, D and Zhu, X and Thorleifsson, G and Helgadottir, A and Gudbjartsson, DF and Holm, H and Olafsson, I and Akiyama, M and Sakaue, S and Terao, C and Kanai, M and Zhou, W and Brumpton, BM and Rasheed, H and Ruotsalainen, SE and Havulinna, AS and Veturi, Y and Feng, QP and Rosenthal, EA and Lingren, T and Pacheco, JA and Pendergrass, SA and Haessler, J and Giulianini, F and Bradford, Y and Miller, JE and Campbell, A and Lin, K and Millwood, IY and Hindy, G and Rasheed, A and Faul, JD and Zhao, W and Weir, DR and Turman, C and Huang, H and Graff, M and Mahajan, A and Brown, MR and Zhang, W and Yu, K and Schmidt, EM and Pandit, A and Gustafsson, S and Yin, S and Luan, J and Zhao, JH and Matsuda, F and Jang, HM and Yoon, K and Medina-Gomez, C and Pitsillides, A and Hottenga, JJ and Willemsen, G and Wood, AR and Ji, Y and Gao, Z and Haworth, S and Mitchell, RE and Chai, JF and Aadahl, M and Yao, J and Manichaikul, A and Warren, HR and Ramirez, J and Bork-Jensen, J and Karhus, LL and Goel, A and Sabater-Lleal, M and Noordam, R and Sidore, C and Fiorillo, E and McDaid, AF and Marques-Vidal, P and Wielscher, M and Trompet, S and Hewitt, AW
Keywords: low frequency, LOCI, meta analysis, cholesterol, ancestry, polymorphisms, discovery, variants, risk, individuals
Journal or Publication Title: Nature
Publisher: Nature
ISSN: 0028-0836
DOI / ID Number: 10.1038/s41586-021-04064-3
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