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A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease

Abstract

Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)1,2,3,4,5,6,7, a modest number considering the apparent heritability of CAD8. All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 × 10−8 in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.

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Figure 1: Studies contributing to the discovery and replication meta-analyses.
Figure 2: Genome-wide Manhattan plot of P values for all studies (European and South Asian).
Figure 3: Newly identified loci and variants associated with CAD in European, South Asian and all studies.
Figure 4: Regional plots for significant associations with CAD.

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Acknowledgements

We are grateful to all of the study participants in the studies contributing to these meta-analyses and to all laboratory staff and former colleagues who have contributed to these studies over many years. This study makes use of data generated by the Wellcome Trust Case-Control Consortium (WTCCC); a full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. This study also makes use of data generated by the UK Twins study, The Twin Research Unit, King's College London, UK.

The PROCARDIS study was supported by the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the British Heart Foundation, the Oxford British Heart Foundation Centre of Research Excellence, the Wellcome Trust (075491/Z/04), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283).

The Heart Protection Study (ISRCTN48489393) was funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co and Roche Vitamins Ltd. Genotyping and analysis was supported by a grant to Oxford University and the Centre National de Génotypage (CNG) from Merck & Co and the Oxford BHF Centre of Research Excellence.

The PROMIS study was funded by unrestricted grants to investigators at the University of Cambridge, UK and at the Centre for Non-Communicable Diseases, Pakistan. Genotyping was funded by the Wellcome Trust.

The LOLIPOP study is supported by the National Institute for Health Research Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, Ealing Hospital NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0700931, G0601966), the Wellcome Trust (084723/Z/08/Z) and the National Institute for Health Research (RP-PG-0407-10371). P.E. is a National Institute for Health Research Senior Investigator. This work was facilitated by Barts and The London National Institute for Health Biomedical Research Unit. We thank the participants and research staff who made the study possible.

The COROGENE-FINRISK study was supported in part by the Aarno Koskelo Foundation and the Finnish Foundation for Cardiovascular Research.

The Biobank of Karolinska Carotid Endarterectomies (BiKE) and Advanced Study of Aortic Pathology (ASAP) eQTL study was supported by the Swedish Heart-Lung Foundation, the Swedish Research Council, the European Commission (FAD, Health-F22008-200647), (AtheroRemo HEALTH-2007-A-201668), DASTI (Danish Agency for Science, Technology and Innovation) and a donation from F. Lundberg.

The Multiple Tissue Human Expression Resource (MuTHER) study was supported by the Wellcome Trust (081917/Z/07/Z).

N. Soranzo is supported by the Wellcome Trust (Core Grant Number 091746/Z/10/Z).

Author information

Authors and Affiliations

Consortia

Contributions

Steering and writing committee: J.F.P., J.C.H., D.S., J.C.C., J.H., N. Soranzo, R. Collins, J.D., P. Elliott, M.F., K.S., W.Z., A. Hamsten, S. Parish, M.L., H.W. (Chair), R. Clarke, P. Deloukas, J.S.K.

Corresponding authors: H.W., D.S., R. Collins, J.S.K.

Analysis committee: J.C.H., W.Z., N. Soranzo, J.F.P., D.S., J.C.C., S. Parish, M.F. (Chair).

Statistical genetics and bioinformatics: HPS: J.C.H., S. Parish; LOLIPOP: W.Z.; PROCARDIS: A. Goel, H.O., R.J.S., S.H., A.M., A. Helgadottir, J.O., M.F., J.F.P.; PROMIS: D.S., K.S., M.M., S. Potter, S.E.H., P. Deloukas.

Genotyping: CNG: J.H., M.D., M.L.; Karolinska: R.J.S.; Oxford: S.J., H.O.; Uppsala: T.A., A.C.S.; WTSI: R.G., S. Bumpsted, E.G., S.E., P.D.

Expression QTL analyses: L.F., T.K., A.F.C., A. Gabrielsen, U.S., the MuTHER consortium, P. Eriksson.

Discovery cohorts: HPS: J.C.H., S. Parish, A.O., R. Clarke, L.B., P.S., J.A., R.P., R. Collins; LOLIPOP: J.C.C., G. Abecasis, N.A., M.C., P. Donnelly, P. Elliott, P.F., A.S.K., M.I.C., N.J.S., J. Scott, J. Sehmi, W.Z., J.S.K.; PROCARDIS: Sweden: A. Silveira, M.L.H., F.M.v.H., G.O., A. Hamsten; Germany: S. Rust, G. Assmann, U.S.; Italy: S. Barlera, G.T., M.G.F.; UK: R. Clarke, P.L., J.C.H., R. Collins, J.F.P., F.R.G., M.F., H.W.; PROMIS: D.S., A.R., M.Z., N. Shah, M.S., N.H.M., M.A., K.S.Z., A. Samad, M. Ishaq, A.R.G., F.M., N.J.S., P.M.F., P.D., J.D.

Replication cohorts: UK Twins: N. Soranzo, T.S.; COROGENE-FINRISK: L.P., M.S.N., J. Sinisalo, V.S., S. Ripatti; ISIS: J.C.H., D.B., S. Parish; SHEEP/SCARF: K.L., B.G., U.d.F.; GISSI-P: S. Pietri, F.G., R.M.; AMC-PAS: S.S., J.J.P.K., M.D.T.; THISEAS: E.V.T., G.V.D.; INTERHEART: J.C.E., S.Y., S.S.A.

For further details on author contributions, see the Supplementary Note.

Corresponding authors

Correspondence to Danish Saleheen, Rory Collins, Hugh Watkins (Chair) or Jaspal S Kooner.

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The author declare no competing financial interests.

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Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note. (PDF 1745 kb)

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The Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 43, 339–344 (2011). https://doi.org/10.1038/ng.782

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