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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Abstract

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

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Figure 1: Graphical summary (Manhattan plot) of genome-wide association results.
Figure 2: Example of overlapping association signals for multiple traits at the ABO gene region on chromosome 9q34.

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Acknowledgements

We thank the participants and staff in each of the studies who contributed to the present article. The sources of funding are listed in the supplementary materials.

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Manuscript writing: H.S., I.R.K., S.K., M.P.R., T.L.A., H.H., A.F.R.S., P. Deloukas, R.R., R.M., J.E., N.J.S.

GWAS meta-analysis samples, genotyping and analysis: H.S., I.R.K., S.K., M.P.R., T.L.A., H.H., M.P., A.F.R.S., M.B., C.G., D. Absher, D. Ardissino, K.A., S.G.B., A.J.B., J.C.B., E.B., P.S.B., M.S.B., L.C., A. Deghan, S.D., P. Diemert, J.D., A. Doering, N.E.E.M., R.E., S.E., M.F., A.R.F., S.G., J.R.G., E.H., A.H., T.I., C.I., M.A.K., J.W.K., A.K., R.L., M.L., W.L., C.L., C.M., T. Meitinger, O.M., V.M., K.M., T. Morgan, J.N., C.P.N., A.P., L.Q., D.J.R., V.S., A. Schäfer, A. Schillert, S.S., J.S., S.M.S., D.S.S., K.S., G. Thorgeirsson, G. Thorleifsson, M.T., A.G.U., B.F.V., G.A.W., H.E.W., C.W., P.S.W., J.C.M.W., B.J.W., T.Z., A.Z., F.C., L.A.C., T.Q., W.M., C.H., S.B., A.S.H., P.D., U.T., R.R., J.R.T., C.J.O., R.M., J.E., N.J.S.

Replication phase samples, genotyping and analysis: H.S., I.R.K., S.K., M.P.R., H.H., M.P., H.A., S.A., K.A., T.L.A., J.L.A., D. Ardissino, D. Absher, T.A.B., L.C.B, D.M.B., K.B., S.M.B., M.J.B., I.B., J.F.C., R.W.D., G.D., R.D., S.G.E., J.C.E., U.d.F., B.G., D.G., V.G., N.H., S.L.H., B.D.H., C.I., G.T.J., J.W.J., L.M.K., J.W.K., J.J.P.K., K.-T.K., G.K., D.L., K.L., P.L.-N., A.J.L., P.M.M., N.M., P.P.M., P.A.M., T. Morgan, T. Meitinger, T.W.M., J.B.M., S.C., M.M.N., O.O., F.P., R.S.P., C.C.P., A.A.Q., L.S.R., F.R.R., D.R., M.L.S., M.S.S., S. Sivapalaratnam, T.B.S., J.D.S., N.S., J.A.S., T.Q., K. Stark, K. Stirrups, M. Stoll, W.H.W.T., A.M.v.R., N.J.W., S.Y., P.D., U.T., R.R., R.M., J.E., N.J.S.

Analysis group: I.R.K., M.P., D. Absher, L.C., E.H., M.L., K.M., A. Schillert, G. Thorleifsson, B.F.V., G.A.W., L.A.C., J.R.T.

Biological analyses: H.S., T.L.A., H.H., M.B., C.G., Z.A., P.S.B., V.C., J.F., S.G., P.L.-N., G.L., S.M., C.R., E.S., M.T., F.C., A.H.G., T.Q., C.H., W.H.O., P.D., U.T., J.E., N.J.S.

CARDIoGRAM consortium executive group: H.S., S.K., M.P.R., J.E., N.J.S.

CARDIoGRAM consortium steering group: H.S., I.R.K., S.K., M.P.R., T.L.A., E.B., R.L., A.Z., C.H., A.S.H., U.T., J.R.T., R.M., J.E., N.J.S.

Corresponding authors

Correspondence to Heribert Schunkert or Nilesh J Samani.

Ethics declarations

Competing interests

Genotyping of PennCATH and Medstar was supported by GlaxoSmithKline. D.M.W., M.C.W. and V.M. are employees of GlaxoSmithKline. H.H., S.G., J.R.G., A.K., K.S., G.T. and U.T. are employees of and/or own stock or stock options in deCODE genetics.

Additional information

A full list of members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 1–14 and Supplementary Note. (PDF 5386 kb)

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Schunkert, H., König, I., Kathiresan, S. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43, 333–338 (2011). https://doi.org/10.1038/ng.784

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