TY - JOUR
T1 - The power of genetic diversity in genome-wide association studies of lipids
AU - VA Million Veteran Program
AU - Global Lipids Genetics Consortium
AU - Graham, Sarah E.
AU - Clarke, Shoa L.
AU - Wu, Kuan Han H.
AU - Kanoni, Stavroula
AU - Zajac, Greg J.M.
AU - Ramdas, Shweta
AU - Surakka, Ida
AU - Ntalla, Ioanna
AU - Vedantam, Sailaja
AU - Winkler, Thomas W.
AU - Locke, Adam E.
AU - Marouli, Eirini
AU - Hwang, Mi Yeong
AU - Han, Sohee
AU - Narita, Akira
AU - Choudhury, Ananyo
AU - Bentley, Amy R.
AU - Ekoru, Kenneth
AU - Verma, Anurag
AU - Trivedi, Bhavi
AU - Martin, Hilary C.
AU - Hunt, Karen A.
AU - Hui, Qin
AU - Klarin, Derek
AU - Zhu, Xiang
AU - Thorleifsson, Gudmar
AU - Helgadottir, Anna
AU - Gudbjartsson, Daniel F.
AU - Holm, Hilma
AU - Olafsson, Isleifur
AU - Akiyama, Masato
AU - Sakaue, Saori
AU - Terao, Chikashi
AU - Kanai, Masahiro
AU - Zhou, Wei
AU - Brumpton, Ben M.
AU - Rasheed, Humaira
AU - Ruotsalainen, Sanni E.
AU - Havulinna, Aki S.
AU - Veturi, Yogasudha
AU - Feng, Qi Ping
AU - Rosenthal, Elisabeth A.
AU - Lingren, Todd
AU - Pacheco, Jennifer Allen
AU - Pendergrass, Sarah A.
AU - Haessler, Jeffrey
AU - Giulianini, Franco
AU - Bradford, Yuki
AU - Lee, Hyejin
AU - Kim, Hyung Lae
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/12/23
Y1 - 2021/12/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85121605114&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04064-3
DO - 10.1038/s41586-021-04064-3
M3 - Article
C2 - 34887591
AN - SCOPUS:85121605114
SN - 0028-0836
VL - 600
SP - 675
EP - 679
JO - Nature
JF - Nature
IS - 7890
ER -