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

Sarah E. Graham, Shoa L. Clarke, VA Million Veteran Program, Global Lipids Genetics Consortium, Kuan Han H. Wu, Stavroula Kanoni, Greg J.M. Zajac, Shweta Ramdas, Ida Surakka, Ioanna Ntalla, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Mi Yeong Hwang, Sohee Han, Akira Narita, Ananyo Choudhury, Amy R. Bentley, Kenneth EkoruAnurag Verma, Bhavi Trivedi, Hilary C. Martin, Karen A. Hunt, Qin Hui, Derek Klarin, Xiang Zhu, Gudmar Thorleifsson, Wei Zhao, Michael R. Brown, Jing Hua Zhao, Carolina Medina-Gomez, Jouke Jan Hottenga, Raymond Noordam, Markus Scholz, Niek Verweij, Phuong Le, Jian Yang, Jun Liu, Ya Xing Wang, Shih Yi Lin, Natalie Terzikhan, Hieab H.H. Adams, M. Arfan Ikram, Torben Hansen, Helena Schmidt, Cornelia M. van Duijn, Tien Yin Wong, Joyce B.J. van Meurs, Mohsen Ghanbari, Paul S. de Vries, Peter Kraft

Research output: Contribution to journalArticleAcademicpeer-review

272 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)675-679
Number of pages5
Issue number7890
Publication statusPublished - 23 Dec 2021

Bibliographical note

Funding Information:
Competing interests G.J.M.Z. is an employee of Incyte Corporation. G.C.-P. is currently an employee of 23andMe. M.J.C. is the Chief Scientist for Genomics England, a UK Government company. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. G.T., A. Helgadottir, D.F.G., H. Holm., U.T. and K. Stefansson are employees of deCODE/Amgen. V.S. has received honoraria for consultations from Novo Nordisk and Sanofi and has an ongoing research collaboration with Bayer. M. McCarthy has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. M. McCarthy and A. Mahajan are employees of Genentech and are holders of Roche stock. M. Scholz receives funding from Pfizer for a project unrelated to this work. M.E.K. is employed by Synlab. W.M. has received grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from Amgen, grants from AstraZeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital, grants from bestbion dx, grants from Boehringer Ingelheim, grants from Immundiagnostik, grants from Merck Chemicals, grants from MSD Sharp and Dohme, grants from Novartis Pharma, grants from Olink Proteomics, and is employed by Synlab Holding Deutschland, all outside the submitted work. A.V.K. has served as a consultant to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen and Color Genomics; received speaking fees from Illumina, the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research; and reports a patent related to a genetic risk predictor (20190017119). S.K. is an employee of Verve Therapeutics and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis and San Therapeutics. He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest and Medscape; and reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). D.K. accepts consulting fees from Regeneron Pharmaceuticals. D.O.M.-K. is a part-time clinical research consultant for Metabolon. D.S. has received support from the British Heart Foundation, Pfizer, Regeneron, Genentech and Eli Lilly pharmaceuticals. The spouse of C.J.W. is employed by Regeneron.

Funding Information:
Acknowledgements Funding for the Global Lipids Genetics Consortium was provided by the NIH (R01-HL127564). This research was conducted using the UK Biobank Resource under application number 24460. Computing support and file management for central meta-analysis by S. Caron is acknowledged. This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by awards 2I01BX003362-03A1 and 1I01BX004821-01A1. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. Study-specific acknowledgements are provided in the Supplementary Information.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.


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