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.

  • Letter
  • Published:

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


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.

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

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Marenberg, M.E., Risch, N., Berkman, L.F., Floderus, B. & de Faire, U. Genetic susceptibility to death from coronary heart disease in a study of twins. N. Engl. J. Med. 330, 1041–1046 (1994).

    Article  CAS  Google Scholar 

  2. Schunkert, H., Erdmann, J. & Samani, N.J. Genetics of myocardial infarction: a progress report. Eur. Heart J. 31, 918–925 (2010).

    Article  Google Scholar 

  3. Preuss, M. et al. Design of the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study: a genome-wide association meta-analysis involving more than 22,000 cases and 60,000 controls. Circ. Cardiovasc. Genet. 3, 475–483 (2010).

    Article  CAS  Google Scholar 

  4. Clarke, R. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518–2528 (2009).

    Article  CAS  Google Scholar 

  5. Trégouët, D.A. et al. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat. Genet. 41, 283–285 (2009).

    Article  Google Scholar 

  6. Psaty, B.M. et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium: design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ. Cardiovasc. Genet. 2, 73–80 (2009).

    Article  Google Scholar 

  7. Nitz, I. et al. Association analyses of GIP and GIPR polymorphisms with traits of the metabolic syndrome. Mol. Nutr. Food Res. 51, 1046–1052 (2007).

    Article  CAS  Google Scholar 

  8. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    Article  CAS  Google Scholar 

  9. Zhong, H. et al. Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes. PLoS Genet. 6, e1000932 (2010).

    Article  Google Scholar 

  10. Ge, B. et al. Global patterns of cis variation in human cells revealed by high-density allelic expression analysis. Nat. Genet. 41, 1216–1222 (2009).

    Article  CAS  Google Scholar 

  11. Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).

    Article  CAS  Google Scholar 

  12. Brown, M.S. & Goldstein, J.L. Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man. Science 185, 61–63 (1974).

    Article  CAS  Google Scholar 

  13. Linsel-Nitschke, P. et al. Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease—a Mendelian Randomisation study. PLoS ONE 3, e2986 (2008).

    Article  Google Scholar 

  14. Musunuru, K. et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–719 (2010).

    Article  CAS  Google Scholar 

  15. Linsel-Nitschke, P., Samani, N.J. & Schunkert, H. Sorting out cholesterol and coronary artery disease. N. Engl. J. Med. 363, 2462–2463 (2010).

    Article  CAS  Google Scholar 

  16. Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

    Article  CAS  Google Scholar 

  17. Wilson, P.W. et al. Prediction of coronary heart disease using risk factor categories. Circulation 97, 1837–1847 (1998).

    Article  CAS  Google Scholar 

  18. 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 

  19. Assimes, T.L. et al. Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Hum. Mol. Genet. 17, 2320–2328 (2008).

    Article  CAS  Google Scholar 

  20. 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 

  21. Samani, N.J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).

    Article  CAS  Google Scholar 

  22. 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 

  23. 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 

  24. Winkelmann, B.R. et al. Rationale and design of the LURIC study—a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2, S1–S73 (2001).

    Article  CAS  Google Scholar 

  25. Lehrke, M. et al. CXCL16 is a marker of inflammation, atherosclerosis and acute coronary syndromes in humans. J. Am. Coll. Cardiol. 49, 442–449 (2007).

    Article  CAS  Google Scholar 

  26. 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 

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

    Article  CAS  Google Scholar 

  28. WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  29. Anonymous. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am. J. Epidemiol. 129, 687–702 (1989).

  30. Wichmann, H.E., Gieger, C. & Illig, T. KORA-gen–resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 67 Suppl 1, S26–S30 (2005).

    Article  Google Scholar 

  31. Pastinen, T. & Hudson, T.J. Cis-acting regulatory variation in the human genome. Science 306, 647–650 (2004).

    Article  CAS  Google Scholar 

  32. Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

    Article  Google Scholar 

  33. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  Google Scholar 

  34. Servin, B. & Stephens, M. Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 3, e114 (2007).

    Article  Google Scholar 

  35. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  Google Scholar 

  36. Bagos, P.G. A unification of multivariate methods for meta-analysis of genetic association studies. Stat. Appl. Genet. Mol. Biol. 7, Article31 (2008).

    Article  Google Scholar 

  37. Bagos, P.G. & Nikolopoulos, G.K. A method for meta-analysis of case-control genetic association studies using logistic regression. Stat. Appl. Genet. Mol. Biol. 6, Article17 (2007).

    Article  Google Scholar 

  38. Gudbjartsson, D.F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).

    Article  CAS  Google Scholar 

  39. Kathiresan, S. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56–65 (2009).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations




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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

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