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Exome chip meta-analysis identifies novel loci and East Asian–specific coding variants that contribute to lipid levels and coronary artery disease

Abstract

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian–specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

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Figure 1: Exome-wide association results for 47,532 East Asians.
Figure 2: The proportion of total trait variance explained by significant and coding variants.
Figure 3: Effect size versus allele frequency for variants associated with blood lipids at exome-wide significance.

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Acknowledgements

We thank all the participants of this study for their contributions. X. Lu is supported by the CAMS Innovation Fund for Medical Sciences (grants 2016-I2M-1-009, 2017-I2M-1-004, and 2016-I2M-1-011) and the National Science Foundation of China (grants 81422043, 91439202, 81370002, 81773537, and 81230069). C.J.W. is supported by the National Institutes of Health (grant HL135824). S.K. and C.J.W. are supported by the National Institutes of Health (grant HL127564). P.C.S. was supported by the Hong Kong Research Grants Council (grants TRS T12/705/11 and GRF 17128515). G.M.P. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (award K01HL125751). We thank P. Marshall for professional editing. Additional acknowledgments of funding sources for the primary studies are provided in Supplementary Note 1.

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Contributions

X. Lu, C.J.W., G.M.P., D.J.L., D.G., and K.L.M. drafted the manuscript. C.J.W., D.G., X. Lu, P.C.S., S.K., K.L.M., and Y.E.C. coordinated the project. X. Lu, D.J.L., G.M.P., and H.Z. served as the central meta-analysis group. X. Lu and J.B.N. carried out eQTL analysis. X. Lu and W. Zhou carried out DeltaSVM analysis. X. Lu, G.M.P., D.J.L., Y. Wu, H.Z., J. Li, C.S.T., R.D., J. Long, X.G., C.N.S., Y.C., Y. Wang, C.Y.Y.C, Q.F., J.S., X.Y., W. Zhao, M.H., and J.B.N. carried out cohort data analysis. W. Zhou, H.L., C.C.K., J. Liu, L.W., F.W., J.S., and W.H. carried out cohort genotyping. H.L., M.X., X. Liu, Y.Z., L.S., Y.G., Y. Hu, K.Y., J.H., Q.C., S.C., A.B.F., L.S.A., P.G.-L., S.D., K.H., and L.G.F. carried out cohort phenotyping. X. Lu, W.H.-H.S., S.S.C., A.B.F., L.S.A., P.G.-L., S.D., R.V., Y.-D.I.C., X.-O.S., K.S.L.L., T.Y.W., S.K.G., Z.M., K.H., L.G.F., H.T., Y. Huo, C.Y.C., Y.E.C., W. Zheng, E.S.T., W.G., X. Lin, W.H., G.A., S.K., K.L.M., T.W., P.C.S., D.G., and C.J.W. were the principal investigators for the cohort.

Corresponding authors

Correspondence to Pak Chung Sham, Dongfeng Gu or Cristen J Willer.

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The authors declare no competing financial interests.

Additional information

A full list of members and affiliations appears in Supplementary Note 1.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1, 2, 4–10, 12,13 and Supplementary Note (PDF 8882 kb)

Life Sciences Reporting Summary (PDF 159 kb)

Supplementary Table 3

Association summary statistics at 38 previously known loci where lead variants reached exome-wide significance (XLSX 20 kb)

Supplementary Table 11

The association of 363 independent variants in the known loci identified by GLGC exome chip study in the East Asian samples (XLSX 62 kb)

Supplementary Table 14

Studies contributing to East Asian meta-analysis (XLSX 12 kb)

Supplementary Table 15

Descriptive statistics for lipid levels across GLGC exome contributing studies (XLSX 19 kb)

Supplementary Table 16

Contributing studies genotyping and analysis information (XLSX 11 kb)

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Lu, X., Peloso, G., Liu, D. et al. Exome chip meta-analysis identifies novel loci and East Asian–specific coding variants that contribute to lipid levels and coronary artery disease. Nat Genet 49, 1722–1730 (2017). https://doi.org/10.1038/ng.3978

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