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

Journal name:
Nature Genetics
Volume:
43,
Pages:
339–344
Year published:
DOI:
doi:10.1038/ng.782
Received
Accepted
Published online

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.

At a glance

Figures

  1. Studies contributing to the discovery and replication meta-analyses.
    Figure 1: Studies contributing to the discovery and replication meta-analyses.

    aIncludes 2,133 cases who are either full or half siblings of another case. bIncludes 2,697 controls from the National Blood Service. cIncludes 2,887 controls from the 1958 British Birth cohort. dIncludes 5,157 controls from the UK Twins study and 2,535 additional independent PROCARDIS controls not used in the discovery analysis.

  2. Genome-wide Manhattan plot of P values for all studies (European and South Asian).
    Figure 2: Genome-wide Manhattan plot of P values for all studies (European and South Asian).

    The −log10 P for 574,919 SNPs from the meta-analysis of the PROCARDIS, HPS, PROMIS and LOLIPOP studies. The y axis is truncated at −log10 P of 12; rs9349379 at the PHACTR1 locus (P = 5.8 × 10−19) and 15 SNPs at the 9p21 locus (7.9 × 10−13 > P > 1.3 × 10−25) exceed the truncation. SNP associations with CAD that exceeded the genome-wide significance threshold (P < 5.0 × 10−8) are shown in magenta; P values between P = 4.5 × 10−5 and P = 5.0 × 10−8 are shown in blue. The locations of the new replicated loci are annotated in black and previously reported CAD loci (Table 1) with P < 4.0 × 10−5 in the meta-analysis of all studies together are annotated in gray.

  3. Newly identified loci and variants associated with CAD in European, South Asian and all studies.
    Figure 3: Newly identified loci and variants associated with CAD in European, South Asian and all studies.

    Odds ratios per copy of the risk allele are indicated by squares (size inversely proportional to the variance), with horizontal lines indicating 95% CIs. Odds ratios and 95% CIs for all participants are indicated by diamonds. Allele frequencies (allele freq) are given for the risk allele. P values for heterogeneity between European and South Asian (S Asian) results are reported (ethnic Phet). *The South Asian only discovery P value for rs4380028 was P = 3.6 × 10−6.

  4. Regional plots for significant associations with CAD.
    Figure 4: Regional plots for significant associations with CAD.

    Regional association plots of the discovery meta-analysis from which each replicated SNP was selected; that is, the European and South Asian discovery meta-analysis (a,b and d,e) and South Asian meta-analysis (c). Each panel shows SNPs plotted by position on the chromosome against –log10 P, with estimated recombination rates from HapMap release 27 (CEU, YRI and JPT+CHB populations) plotted in light blue to reflect the local LD structure on a secondary y axis. The most significant lead SNP (red diamond) at each locus is annotated with its discovery P value, and flanking SNPs are color-coded to represent the pairwise r2 measure of LD with the lead SNP: blue, r2 ≥ 0.8; green, 0.5 ≤ r2 < 0.8; orange, 0.2 ≤ r2 ≤ 0.5; gray, r2 < 0.2. a,b and d,e report r2 values calculated from HapMap2 CEU reference samples, and c reports r2 values calculated from HapMap2 GIH reference samples. Green bars represent RefSeq genes in the region. All positions are on NCBI build 36. The purple star in b represents significant eQTL association in aortic media. The black arrowhead in c represents the South Asian only meta-analysis P value.

References

  1. Erdmann, J. et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat. Genet. 41, 280282 (2009).
  2. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 14911493 (2007).
  3. Kathiresan, S. et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334341 (2009).
  4. McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 14881491 (2007).
  5. Samani, N.J. et al. Genome-wide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443453 (2007).
  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, 11821190 (2009).
  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, 661678 (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, 247254 (2002).
  9. Reich, D., Thangaraj, K., Patterson, N., Price, A.L. & Singh, L. Reconstructing Indian population history. Nature 461, 489494 (2009).
  10. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904909 (2006).
  11. Zeller, T. et al. Genetics and beyond–the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).
  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, 415423 (2009).
  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, H442H452 (2009).
  14. Wang, L. et al. ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries. Circ. Res. 104, 688698 (2009).
  15. Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42, 441447 (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, H509H521 (2008).
  17. Brindley, D.N. & Pilquil, C. Lipid phosphate phosphatases and signaling. J. Lipid Res. 50 Suppl, S225S230 (2009).
  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, 15931606 (2010).
  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, 16751684 (2008).
  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, 383292 (2011).
  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, 158168 (2011).
  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, 806814 (2008).
  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, 722 (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, 329338 (2009).
  25. Chambers, J.C. et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat. Genet. 40, 716718 (2008).
  26. Ripatti, S. et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376, 13931400 (2010).
  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).
  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, 161174 (1999).
  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, 411419 (2005).
  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, 770774 (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, 447455 (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, 773775 (2002).
  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).
  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, 23902398 (2010).
  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, 365373 (2010).
  36. Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 12171224 (2007).

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Author information

  1. These authors contributed equally to this work.

    • John F Peden,
    • Jemma C Hopewell,
    • Danish Saleheen,
    • John C Chambers,
    • Jorg Hager,
    • Nicole Soranzo,
    • Rory Collins,
    • John Danesh,
    • Paul Elliott,
    • Martin Farrall,
    • Kathy Stirrups,
    • Weihua Zhang,
    • Anders Hamsten,
    • Sarah Parish,
    • Mark Lathrop,
    • Hugh Watkins (Chair),
    • Robert Clarke,
    • Panos Deloukas &
    • Jaspal S Kooner

Affiliations

  1. Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • John F Peden,
    • Martin Farrall,
    • Hugh Watkins,
    • Anuj Goel,
    • Halit Ongen,
    • Anna Helgadottir,
    • Shapour Jalilzadeh &
    • Theodosios Kyriakou
  2. Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.

    • John F Peden,
    • Martin Farrall,
    • Hugh Watkins,
    • Anuj Goel,
    • Halit Ongen,
    • Anna Helgadottir,
    • Shapour Jalilzadeh,
    • Theodosios Kyriakou &
    • Peter Sleight
  3. Clinical Trial Service Unit, University of Oxford, Oxford, UK.

    • Jemma C Hopewell,
    • Rory Collins,
    • Sarah Parish,
    • Robert Clarke,
    • Alison Offer,
    • Louise Bowman,
    • Jane Armitage,
    • Richard Peto,
    • Pamela Linksted &
    • Derrick Bennett
  4. Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.

    • Danish Saleheen,
    • Asif Rasheed,
    • Moazzam Zaidi,
    • Nabi Shah,
    • Maria Samuel &
    • Philippe M Frossard
  5. Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Danish Saleheen &
    • John Danesh
  6. Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK.

    • John C Chambers,
    • Paul Elliott &
    • Weihua Zhang
  7. Cardiology, Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.

    • John C Chambers,
    • Weihua Zhang &
    • Jaspal S Kooner
  8. Commissariat à l′Energie Atomique (CEA) Genomics Institute-Centre National de Génotypage, Evry Cedex, France.

    • Jorg Hager,
    • Mark Lathrop,
    • Simon Heath &
    • Marc Delepine
  9. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Nicole Soranzo,
    • Kathy Stirrups,
    • Panos Deloukas,
    • Muhammed Murtaza &
    • Leena Peltonen
  10. Medical Research Council-Health Protection Agency (MRC-HPA) Centre for Environment and Health, Imperial College London, London, UK.

    • Paul Elliott
  11. Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Anders Hamsten,
    • Rona J Strawbridge,
    • Anders Mälarstig,
    • John Öhrvik,
    • Lasse Folkersen,
    • Per Eriksson,
    • Angela Silveira &
    • Ferdinand M van 't Hooft
  12. Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.

    • Anders Hamsten,
    • Rona J Strawbridge,
    • Anders Mälarstig,
    • John Öhrvik,
    • Lasse Folkersen,
    • Per Eriksson,
    • Angela Silveira &
    • Ferdinand M van 't Hooft
  13. National Heart and Lung Institute, Imperial College London, London, UK.

    • Jaspal S Kooner,
    • James Scott &
    • Joban Sehmi
  14. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Simon Potter,
    • Sarah E Hunt,
    • Rhian Gwilliam,
    • Suzannah Bumpstead,
    • Emma Gray &
    • Sarah Edkins
  15. Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden.

    • Tomas Axelsson &
    • Ann-Christine Syvanen
  16. Thoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Anders Franco-Cereceda
  17. Cardiology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Anders Gabrielsen
  18. Gesellschaft für Arterioskleroseforschung e.V., Leibniz-Institut für Arterioskleroseforschung an der Universität Münster (LIFA), Münster, Germany.

    • Udo Seedorf,
    • Stephan Rust &
    • Gerd Assmann
  19. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Goncalo Abecasis
  20. Cardiology, Ealing Hospital NHS Trust, Middlesex, UK.

    • Nabeel Ahmed &
    • Angad S Kooner
  21. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Mark Caulfield
  22. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Peter Donnelly &
    • Mark I McCarthy
  23. Department of Statistics, Oxford University, Oxford, UK.

    • Peter Donnelly
  24. Genomic Medicine, Imperial College London, London, UK.

    • Philippe Froguel
  25. Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Oxford, UK.

    • Mark I McCarthy
  26. Oxford National Institute of Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Headington, UK.

    • Mark I McCarthy
  27. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.

    • Nilesh J Samani
  28. Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.

    • Nilesh J Samani
  29. Cardiology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Mai-Lis Hellénius
  30. Cardiovascular Drug Research at the Department of Medicine, Solna, Sweden.

    • Gunnar Olsson
  31. Cardiovascular and Gastrointestinal Innovative Medicines, Global Research and Development, AstraZeneca, Sweden.

    • Gunnar Olsson
  32. Department of Cardiovascular Research, Istituto Mario Negri, Milano, Italy.

    • Simona Barlera,
    • Gianni Tognoni,
    • Maria Grazia Franzosi,
    • Silvia Pietri &
    • Francesca Gori
  33. Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy.

    • Gianni Tognoni
  34. Biochemical Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guilford, UK.

    • Fiona R Green
  35. Department of Cardiology, Punjab Institute of Cardiology, Jail Road, Lahore, Pakistan.

    • Nadeem H Mallick &
    • Muhammad Azhar
  36. Department of Cardiology, National Institute of Cardiovascular Diseases, Karachi, Pakistan.

    • Khan S Zaman
  37. Department of Cardiology, Karachi Institute of Heart Diseases, Federal B. Area, Karachi, Pakistan.

    • Abdus Samad &
    • Mohammad Ishaq
  38. Department of Cardiology, Ch. Pervaiz Elahi Institute Of Cardiology, Multan, Pakistan.

    • Ali R Gardezi
  39. Department of Cardiology, Red Crescent Institute of Cardiology, Latifabad, Hyderabad, Pakistan.

    • Fazal-ur-Rehman Memon
  40. Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.

    • Tim Spector
  41. Department of Medical Genetics, University of Helsinki and the Helsinki University Central Hospital, Helsinki, Finland.

    • Leena Peltonen
  42. Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.

    • Markku S Nieminen
  43. University Central Hospital, Cardiovascular Laboratory, Helsinki, Finland.

    • Juha Sinisalo
  44. National Institute for Health and Welfare, Helsinki, Finland.

    • Veikko Salomaa &
    • Samuli Ripatti
  45. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Leena Peltonen &
    • Samuli Ripatti
  46. Cardiovascular Epidemiology Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Karin Leander,
    • Bruna Gigante &
    • Ulf de Faire
  47. Laboratory of Clinical Epidemiology of Cardiovascular Disease, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.

    • Roberto Marchioli
  48. Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • Suthesh Sivapalaratnam,
    • John J P Kastelein &
    • Mieke D Trip
  49. Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.

    • Eirini V Theodoraki &
    • George V Dedoussis
  50. McGill University Department of Medicine, Montreal, Quebec, Canada.

    • Jamie C Engert
  51. McGill University Department of Human Genetics, Montreal, Quebec, Canada.

    • Jamie C Engert
  52. Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Canada.

    • Salim Yusuf &
    • Sonia S Anand
  53. Department of Medicine, McMaster University, Hamilton, Canada.

    • Sonia S Anand

Consortia

  1. The Coronary Artery Disease (C4D) Genetics Consortium

  2. Steering and Writing committee

    • John F Peden,
    • Jemma C Hopewell,
    • Danish Saleheen,
    • John C Chambers,
    • Jorg Hager,
    • Nicole Soranzo,
    • Rory Collins,
    • John Danesh,
    • Paul Elliott,
    • Martin Farrall,
    • Kathy Stirrups,
    • Weihua Zhang,
    • Anders Hamsten,
    • Sarah Parish,
    • Mark Lathrop,
    • Hugh Watkins (Chair),
    • Robert Clarke,
    • Panos Deloukas &
    • Jaspal S Kooner
  3. Statistical genetics and bioinformatics

    • Anuj Goel,
    • Halit Ongen,
    • Rona J Strawbridge,
    • Simon Heath,
    • Anders Mälarstig,
    • Anna Helgadottir,
    • John Öhrvik,
    • Muhammed Murtaza,
    • Simon Potter &
    • Sarah E Hunt
  4. Genotyping

    • Marc Delepine,
    • Shapour Jalilzadeh,
    • Tomas Axelsson,
    • Ann-Christine Syvanen,
    • Rhian Gwilliam,
    • Suzannah Bumpstead,
    • Emma Gray &
    • Sarah Edkins
  5. Expression QTL analyses

    • Lasse Folkersen,
    • Theodosios Kyriakou,
    • Anders Franco-Cereceda,
    • Anders Gabrielsen,
    • Udo Seedorf,
    • Per Eriksson &
    • the MuTHER consortium
  6. Discovery cohorts

    • Alison Offer,
    • Louise Bowman,
    • Peter Sleight,
    • Jane Armitage,
    • Richard Peto,
    • Goncalo Abecasis,
    • Nabeel Ahmed,
    • Mark Caulfield,
    • Peter Donnelly,
    • Philippe Froguel,
    • Angad S Kooner,
    • Mark I McCarthy,
    • Nilesh J Samani,
    • James Scott,
    • Joban Sehmi,
    • Angela Silveira,
    • Mai-Lis Hellénius,
    • Ferdinand M van 't Hooft,
    • Gunnar Olsson,
    • Stephan Rust,
    • Gerd Assmann,
    • Simona Barlera,
    • Gianni Tognoni,
    • Maria Grazia Franzosi,
    • Pamela Linksted,
    • Fiona R Green,
    • Asif Rasheed,
    • Moazzam Zaidi,
    • Nabi Shah,
    • Maria Samuel,
    • Nadeem H Mallick,
    • Muhammad Azhar,
    • Khan S Zaman,
    • Abdus Samad,
    • Mohammad Ishaq,
    • Ali R Gardezi,
    • Fazal-ur-Rehman Memon &
    • Philippe M Frossard
  7. Replication cohorts

    • Tim Spector,
    • Leena Peltonen,
    • Markku S Nieminen,
    • Juha Sinisalo,
    • Veikko Salomaa,
    • Samuli Ripatti,
    • Derrick Bennett,
    • Karin Leander,
    • Bruna Gigante,
    • Ulf de Faire,
    • Silvia Pietri,
    • Francesca Gori,
    • Roberto Marchioli,
    • Suthesh Sivapalaratnam,
    • John J P Kastelein,
    • Mieke D Trip,
    • Eirini V Theodoraki,
    • George V Dedoussis,
    • Jamie C Engert,
    • Salim Yusuf &
    • Sonia S Anand

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.

Steering and Writing committee: John F Peden1,2,54, Jemma C Hopewell3,54, Danish Saleheen4,5,54, John C Chambers6,7,54, Jorg Hager8,54, Nicole Soranzo9,54, Rory Collins3,54, John Danesh5,54, Paul Elliott6,10,54, Martin Farrall1,2,54, Kathy Stirrups9,54, Weihua Zhang6,7,54, Anders Hamsten11,12,54, Sarah Parish3,54, Mark Lathrop8,54, Hugh Watkins (Chair) 1,2,54, Robert Clarke3,54, Panos Deloukas9,54 & Jaspal S Kooner7,13,54,

Statistical genetics and bioinformatics: Anuj Goel1,2, Halit Ongen1,2, Rona J Strawbridge11,12, Simon Heath8, Anders Mälarstig11,12, Anna Helgadottir1,2, John Öhrvik11,12, Muhammed Murtaza9, Simon Potter14 & Sarah E Hunt14

Genotyping: Marc Delepine8, Shapour Jalilzadeh1,2, Tomas Axelsson15, Ann-Christine Syvanen15, Rhian Gwilliam14, Suzannah Bumpstead14, Emma Gray14 & Sarah Edkins14

Expression QTL analyses: Lasse Folkersen11,12, Theodosios Kyriakou1,2, Anders Franco-Cereceda16, Anders Gabrielsen17, Udo Seedorf18, the MuTHER consortium & Per Eriksson11,12

Discovery cohorts: Alison Offer3, Louise Bowman3, Peter Sleight2, Jane Armitage3, Richard Peto3, Goncalo Abecasis19, Nabeel Ahmed20, Mark Caulfield21, Peter Donnelly22,23, Philippe Froguel24, Angad S Kooner20, Mark I McCarthy22,25,26, Nilesh J Samani27,28, James Scott13, Joban Sehmi13, Angela Silveira11,12, Mai-Lis Hellénius29, Ferdinand M van 't Hooft11,12, Gunnar Olsson30,31, Stephan Rust18, Gerd Assmann18, Simona Barlera32, Gianni Tognoni32,33, Maria Grazia Franzosi32, Pamela Linksted3, Fiona R Green34, Asif Rasheed4, Moazzam Zaidi4, Nabi Shah4, Maria Samuel4, Nadeem H Mallick35, Muhammad Azhar35, Khan S Zaman36, Abdus Samad37, Mohammad Ishaq37, Ali R Gardezi38, Fazal-ur-Rehman Memon39 & Philippe M Frossard4

Replication cohorts: Tim Spector40, Leena Peltonen9,41,45, Markku S Nieminen42, Juha Sinisalo43, Veikko Salomaa44, Samuli Ripatti44,45, Derrick Bennett3, Karin Leander46, Bruna Gigante46, Ulf de Faire46, Silvia Pietri32, Francesca Gori32, Roberto Marchioli47, Suthesh Sivapalaratnam48, John J P Kastelein48, Mieke D Trip48, Eirini V Theodoraki49, George V Dedoussis49, Jamie C Engert50,51, Salim Yusuf52 & Sonia S Anand52,53

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      Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note.

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