The power of genetic diversity in genome-wide association studies of lipids
Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , he...
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| Published in | Nature (London) Vol. 600; no. 7890; pp. 675 - 679 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group UK
23.12.2021
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Summary: | Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use
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. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels
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, heart disease remains the leading cause of death worldwide
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. 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 GWAS
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–
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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 patterns
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. 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 medicine
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, we anticipate that increased diversity of participants will lead to more accurate and equitable
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application of polygenic scores in clinical practice.
A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size. |
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| Bibliography: | S.L.C., K-H.H.W., S.K., G.J.M.Z., S.R. contributed equally to this work (as co-second authors). All authors reviewed the manuscript. Consortium management: G.M.P., P.N., T.L.A., M.B., S.K., C.J.W. Study design, interpretation of results, and drafting of manuscript: S.E.G., S.L.C., K-H.H.W., S.K., G.J.M.Z., S.R., I.S., I.N., E.M., K.L.M., T.M.F., J.N.H., S.K., M.B., P.N., G.M.P., C.D.B., A.P.M., Y.V.S., P.D., T.L.A., C.J.W. Primary meta-analysis and quality control: S.E.G., S.V., T.W.W., A.E.L. Polygenic score analysis and development: S.E.G., S.L.C., K-H.H.W., S.K., M.Y.H., S.H., A.N., A.C., A.R.B., K.E., A.V., B.T., H.C.M., K.A.H., C.N.R., S.H., M.R., R.C.T., D.A.vH., G.T., M.Y., B-J.K. Individual study genetic analysis: S.E.G., S.K., S.V., A.E.L., K.L.M., G.M.P., P.D., C.J.W., Q.H., D.K., X.Z., G.T., A.H., D.F.G., H.H., I.O., M.A., S.S., C.T., M.K., W.Z., B.M.B., H.R., S.E.R., A.S.H., Y.V., Q.F., E.A.R., T.L., J.A.P., S.A.P., J.H., F.G., Y.B., J.E.M., A.C., K.L., I.Y.M., G.H., A.R., J.D.F., W.Z., D.R.W., C.T., H.H., M.G., A.M., M.R.B., W.Z., K.Y., E.M.S., A.P., S.G., X.Y., J.L., J.Z., F.M., H.J., K.Y., C.M., A.P., J.H., G.W., A.R.W., Y.J., Z.G., S.H., R.E.M., J.C., M.A., J.Y., A.M., H.R.W., J.R., J.B., L.L.K., A.G., M.S., R.N., C.S., E.F., A.F.M., P.M., M.W., S.T., N.S., L.T.M., B.H.T., M.M., L.Z., J.H., B.Y., A.P., A.K., C.L., L.F., M.S., T.E.G., J.P.B., E.W.D., J.M.Z., J.S.M., C.F., H.C., J.A.B., M.F.F., M.K.W., M.P., M.M., P.C., N.V., J.W.B., J.E., R.L.K., R.C.S., K.L., N.R.Z., P.L., M.E.K., G.E.D., S.H., D.D.I., H.I., J.Y., J.L., H.L.L., J.M., B.S., M.A., L.J.S., M.C., C.W., M.N., A.W., N.H., X.S., R.X., A.H., J.C.F., V.L., M.A., A.U.J., M.R.I., C.O., H.K., S.R., P.R.T., L.A., R.D., L.A.L., X.C., G.P., L.L., M.P., J.L., X.L., E.T., F.T., C.N.S., A.L., S.B., S.C.W., Y.W., W.B.W., T.N., D.R., Y.S., Y.H., S.C., F.L., J.Y., K.A.K., M.G., M.B., K.M., L.F.B., J.A.S., P.H., A.F., E.H., M.L., C.X., J.Z., M.C., S.V., P.J.v., N.P., B.E.C., J.L., S.v., K.C., S.W., M.E.Z., J.L., H.C., M.N., S.F., L.S., N.W.R., C.A.W., S.L., J.W., C.C., L.L., K.N., G.C., H.V., B.H., O.G., Q.C., M.O.O., J.v., X.L., K.S., N.T., J.S., R.D.J., A.P.R., L.W.M., Z.C., L.L., H.M.H., K.L.Y., T.K., J.T., J.C.B., G.N.N., L.J.L., H.L., M.A.N., O.T.R., S.I., S.H.W., C.P.N., H.C., S.J., T.N., F.A., H.N., P.S.B., I.K., P.K., T.G., T.K., K.B., D.d., G.d., E.K., H.H.A., M.I., X.Z., F.W.A., A.O.K., J.W.B., X.S., L.S.R., O.P., T.H., P.M., A.W.H., M.K., L.P., C.B., A.T., Y.C., C.E.P., T.A.M., W.L., A.F., C.O., D.M., Y.C., H.L., J.Y., W.K., S.R., J.W., I.M.H., K.J.S., H.V., G.H., M.K.E., A.B.Z., O.P., G.P., I.E.H., S.R., K.P., A.J.O., H.S., G.B., R.S., H.S., Y.E.C., S.B., G.D., T.T., S.L.K., N.K., M.B.S., G.G., B.J., C.A.B., P.K.J., D.A.B., P.L.D., X.L., V.M., M.B., M.J.C., P.B.M., X.G., M.C., J.B.J., N.J.S., D.I.C., J.K., P.P., T.T., C.A.A., L.S.A., S.A.B., H.d., A.R.W., R.K., J.W., W.Z., A.I.d., D.B., A.C., J.G.W., L.L., C.H., A.E.N., Y.M.G., J.F.W., B.P., H.K., J.A., R.J.S., D.C.R., D.K.A., M.W., H.A.K., G.R.C., C.S.Y., J.M.M., T.T., C.A., C.G.V., L.O., M.F., E.T., R.M.v., T.L., N.C., M.Y., J.L., D.F.R., A.M., F.K., K.J., M.I.M., C.N.P., V.V., C.H., E.S., C.M.v., F.L., J.Q., H.H., X.L., W.M., E.J.P., M.C., V.G., J.T., G.L., L.M.t., P.J.E., D.J.R., S.M.D., M.K., M.K., P.v., T.D.S., R.J.L., M.A.P., B.M.P., I.B., P.P.P., K.C., S.R., E.W., H.H., S.F.G., L.A.K., J.d., M.L., F.K., D.G., J.E., H.S., P.W.F., A.L., J.W.J., A.V.K., M.M., M.J., Z.K., F.C., D.O.M., K.W., H.W., D.P.S., N.G., P.S., N.P., J.I.R., T.M.D., F.K., M.J.N., N.J.T., C.C., T.W., C.K., C.S., A.P., C.G., A.T.H., N.L.P., P.K.M., D.I.B., E.J.d., L.A.C., J.B.v., M.G., P.G., W.H., Y.K., Y.T., N.J.W., C.L., E.Z., J.K., M.L., E.I., G.A., J.C.C., J.S.K., P.S.d., A.C.M., K.E.N., M.D., P.K., N.G.M., J.B.W., S.A., D.S., R.G.W., M.V.H., C.B., B.H.S., A.E.J., A.B., J.E.B., P.M.R., D.I.C., C.K., W.W., G.P.J., B.N., M.H., M.D.R., P.J., V.S., K.H., B.Å., M.K., Y.K., Y.O., Y.M., U.T., K.S., Y.H., J.A.L., D.R., P.S.T., K.C., K.C., C.J.O., J.M.G., P.W. These authors jointly supervised this work Present Address: Genentech, 1 DNA Way, South San Francisco, CA 94080 A full list of consortia members can be found in the supplementary information Author Contributions |
| ISSN: | 0028-0836 1476-4687 1476-4687 |
| DOI: | 10.1038/s41586-021-04064-3 |