Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Erdmann, J. et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41, 280–282 (2009).

    Article  CAS  Google Scholar 

  2. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).

    Article  CAS  Google Scholar 

  3. Kathiresan, S. et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009).

    Article  CAS  Google Scholar 

  4. McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).

    Article  CAS  Google Scholar 

  5. Samani, N.J. et al. Genome-wide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).

    Article  CAS  Google Scholar 

  6. Soranzo, N. et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat. Genet. 41, 1182–1190 (2009).

    Article  CAS  Google Scholar 

  7. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  8. Zdravkovic, S. et al. Heritability of death from coronary heart disease: a 36-year follow-up of 20 966 Swedish twins. J. Intern. Med. 252, 247–254 (2002).

    Article  CAS  Google Scholar 

  9. Reich, D., Thangaraj, K., Patterson, N., Price, A.L. & Singh, L. Reconstructing Indian population history. Nature 461, 489–494 (2009).

    Article  CAS  Google Scholar 

  10. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  11. Zeller, T. et al. Genetics and beyond–the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).

    Article  Google Scholar 

  12. Wagsater, D., Zhu, C., Bjorck, H.M. & Eriksson, P. Effects of PDGF-C and PDGF-D on monocyte migration and MMP-2 and MMP-9 expression. Atherosclerosis 202, 415–423 (2009).

    Article  Google Scholar 

  13. Thomas, J.A. et al. PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns. Am. J. Physiol. Heart Circ. Physiol. 296, H442–H452 (2009).

    Article  CAS  Google Scholar 

  14. Wang, L. et al. ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries. Circ. Res. 104, 688–698 (2009).

    Article  CAS  Google Scholar 

  15. Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42, 441–447 (2010).

  16. Adams, J.W. et al. Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor. Am. J. Physiol. Heart Circ. Physiol. 295, H509–H521 (2008).

    Article  CAS  Google Scholar 

  17. Brindley, D.N. & Pilquil, C. Lipid phosphate phosphatases and signaling. J. Lipid Res. 50 Suppl, S225–S230 (2009).

    Article  Google Scholar 

  18. Humtsoe, J.O., Liu, M., Malik, A.B. & Wary, K.K. Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures. Mol. Cell. Biol. 30, 1593–1606 (2010).

    Article  CAS  Google Scholar 

  19. Schunkert, H. et al. Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation 117, 1675–1684 (2008).

    Article  Google Scholar 

  20. Reilly, M.P. et al. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377, 383–292 (2011).

    Article  CAS  Google Scholar 

  21. Erdmann, J. et al. Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23. Eur. Heart J. 32, 158–168 (2011).

    Article  CAS  Google Scholar 

  22. Broadbent, H.M. et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum. Mol. Genet. 17, 806–814 (2008).

    Article  CAS  Google Scholar 

  23. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 7–22 (2002).

  24. Saleheen, D. et al. The Pakistan Risk of Myocardial Infarction Study: a resource for the study of genetic, lifestyle and other determinants of myocardial infarction in South Asia. Eur. J. Epidemiol. 24, 329–338 (2009).

    Article  Google Scholar 

  25. Chambers, J.C. et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat. Genet. 40, 716–718 (2008).

    Article  CAS  Google Scholar 

  26. Ripatti, S. et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376, 1393–1400 (2010).

    Article  Google Scholar 

  27. Clarke, R. et al. Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study. PLoS Genet. 2, e107 (2006).

    Article  Google Scholar 

  28. Reuterwall, C. et al. Higher relative, but lower absolute risks of myocardial infarction in women than in men: analysis of some major risk factors in the SHEEP study. The SHEEP Study Group. J. Intern. Med. 246, 161–174 (1999).

    Article  CAS  Google Scholar 

  29. Samnegard, A. et al. Serum matrix metalloproteinase-3 concentration is influenced by MMP-3 -1612 5A/6A promoter genotype and associated with myocardial infarction. J. Intern. Med. 258, 411–419 (2005).

    Article  CAS  Google Scholar 

  30. PROCARDIS Consortium. A trio family study showing association of the lymphotoxin-alpha N26 (804A) allele with coronary artery disease. Eur. J. Hum. Genet. 12, 770–774 (2004).

  31. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 354, 447–455 (1999).

  32. Trip, M.D. et al. Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease. Circulation 106, 773–775 (2002).

    Article  CAS  Google Scholar 

  33. Theodoraki, E.V. et al. Fibrinogen beta variants confer protection against coronary artery disease in a Greek case-control study. BMC Med. Genet. 11, 28 (2010).

    Article  Google Scholar 

  34. Mente, A. et al. Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries. J. Am. Coll. Cardiol. 55, 2390–2398 (2010).

    Article  Google Scholar 

  35. Folkersen, L. et al. Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease. Circ. Cardiovasc. Genet. 3, 365–373 (2010).

    Article  CAS  Google Scholar 

  36. Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).

    Article  CAS  Google Scholar 

Download references


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 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



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.

Ethics declarations

Competing interests

The author declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing