Published at www.nejm.org July 18, 2007 (10.1056/NEJMoa072366)
Genomewide Association Analysis of Coronary Artery Disease
Nilesh J. Samani, F.Med.Sci., Jeanette Erdmann, Ph.D., Alistair S. Hall, F.R.C.P., Christian Hengstenberg, M.D., Massimo Mangino, Ph.D., Bjoern Mayer, M.D., Richard J. Dixon, Ph.D., Thomas Meitinger, M.D., Peter Braund, M.Sc., H.-Erich Wichmann, M.D., Jennifer H. Barrett, Ph.D., Inke R. König, Ph.D., Suzanne E. Stevens, M.Sc., Silke Szymczak, M.Sc., David-Alexandre Tregouet, Ph.D., Mark M. Iles, Ph.D., Friedrich Pahlke, M.Sc., Helen Pollard, M.Sc., Wolfgang Lieb, M.D., Francois Cambien, M.D., Marcus Fischer, M.D., Willem Ouwehand, F.R.C.Path., Stefan Blankenberg, M.D., Anthony J. Balmforth, Ph.D., Andrea Baessler, M.D., Stephen G. Ball, F.R.C.P., Tim M. Strom, M.D., Ingrid Brænne, M.Sc., Christian Gieger, Ph.D., Panos Deloukas, Ph.D., Martin D. Tobin, M.F.P.H.M., Andreas Ziegler, Ph.D., John R. Thompson, Ph.D., Heribert Schunkert, M.D., for the WTCCC and the Cardiogenics Consortium
Background Modern genotyping platforms permit a systematic searchfor inherited components of complex diseases. We performed ajoint analysis of two genomewide association studies of coronaryartery disease.
Methods We first identified chromosomal loci that were stronglyassociated with coronary artery disease in the Wellcome TrustCase Control Consortium (WTCCC) study (which involved 1926 casesubjects with coronary artery disease and 2938 controls) andlooked for replication in the German MI [Myocardial Infarction]Family Study (which involved 875 case subjects with myocardialinfarction and 1644 controls). Data on other single-nucleotidepolymorphisms (SNPs) that were significantly associated withcoronary artery disease in either study (P<0.001) were thencombined to identify additional loci with a high probabilityof true association. Genotyping in both studies was performedwith the use of the GeneChip Human Mapping 500K Array Set (Affymetrix).
Results Of thousands of chromosomal loci studied, the same locushad the strongest association with coronary artery disease inboth the WTCCC and the German studies: chromosome 9p21.3 (SNP,rs1333049) (P=1.80x10–14 and P=3.40x10–6, respectively).Overall, the WTCCC study revealed nine loci that were stronglyassociated with coronary artery disease (P<1.2x10–5and less than a 50% chance of being falsely positive). In additionto chromosome 9p21.3, two of these loci were successfully replicated(adjusted P<0.05) in the German study: chromosome 6q25.1(rs6922269) and chromosome 2q36.3 (rs2943634). The combinedanalysis of the two studies identified four additional locisignificantly associated with coronary artery disease (P<1.3x10–6)and a high probability (>80%) of a true association: chromosomes1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and15q22.33 (rs17228212).
Conclusions We identified several genetic loci that, individuallyand in aggregate, substantially affect the risk of developmentof coronary artery disease.
Source Information
From the University of Leicester, Leicester (N.J.S., M.M., R.J.D., P.B., S.E.S., H.P., M.D.T., J.R.T.); University of Leeds, Leeds (A.S.H., J.H.B., M.M.I., A.J.B., S.G.B.); University of Cambridge and National Health Service Blood and Transplant, Cambridge (W.O.); and the Wellcome Trust Sanger Institute, Hinxton (P.D.) — all in the United Kingdom; Universität zu Lübeck, Lübeck (J.E., B.M., I.R.K., S.S., F.P., W.L., I.B., A.Z., H.S.); Universität Regensburg, Regensburg (C.H., M.F., A.B.); GSF–Nationales Forschungszentrum für Umwelt und Gesundheit, Neuherberg (T.M., H.-E.W., T.M.S., C.G.); Technische Universität München, Munich (T.M.); Ludwig Maximilians University, Munich (H.-E.W., C.G.); and Johannes Gutenberg University Mainz, Mainz (S.B.) — all in Germany; and INSERM, UMR S525, Université Pierre et Marie Curie, Paris (D.-A.T., F.C.). This article (10.1056/NEJMoa072366) was published at www.nejm.org on July 18, 2007. It will appear in the August 2 issue of the Journal.
Address reprint requests to Dr. Samani at the Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, United Kingdom, or at njs{at}le.ac.uk or to Dr. Schunkert at Medizinische Klinik II, Universität zu Lübeck, 23538 Lübeck, Germany, or at heribert.schunkert{at}innere2.uni-luebeck.de.
Mohlke, K. L., Boehnke, M., Abecasis, G. R.
(2008). Metabolic and cardiovascular traits: an abundance of recently identified common genetic variants. Hum Mol Genet
17: R102-R108
[Abstract][Full Text]
Edmondson, A. C., Rader, D. J.
(2008). Genome-Wide Approaches to Finding Novel Genes for Lipid Traits: The Start of a Long Road. Circ Cardiovasc Genet
1: 3-6
[Full Text]
Chasman, D. I., Pare, G., Zee, R. Y.L., Parker, A. N., Cook, N. R., Buring, J. E., Kwiatkowski, D. J., Rose, L. M., Smith, J. D., Williams, P. T., Rieder, M. J., Rotter, J. I., Nickerson, D. A., Krauss, R. M., Miletich, J. P., Ridker, P. M
(2008). Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication. Circ Cardiovasc Genet
1: 21-30
[Abstract][Full Text]
Bown, M. J., Braund, P. S., Thompson, J., London, N. J.M., Samani, N. J., Sayers, R. D.
(2008). Association Between the Coronary Artery Disease Risk Locus on Chromosome 9p21.3 and Abdominal Aortic Aneurysm. Circ Cardiovasc Genet
1: 39-42
[Abstract][Full Text]
O'Donnell, C. J., Nabel, E. G.
(2008). Cardiovascular Genomics, Personalized Medicine, and the National Heart, Lung, and Blood Institute: Part I: The Beginning of an Era. Circ Cardiovasc Genet
1: 51-57
[Full Text]
Musunuru, K., Kathiresan, S.
(2008). HapMap and Mapping Genes for Cardiovascular Disease. Circ Cardiovasc Genet
1: 66-71
[Full Text]
Zhong, H., Prentice, R. L.
(2008). Bias-reduced estimators and confidence intervals for odds ratios in genome-wide association studies. Biostatistics
9: 621-634
[Abstract][Full Text]
Sarasquete, M. E., Garcia-Sanz, R., Marin, L., Alcoceba, M., Chillon, M. C., Balanzategui, A., Santamaria, C., Rosinol, L., de la Rubia, J., Hernandez, M. T., Garcia-Navarro, I., Lahuerta, J. J., Gonzalez, M., San Miguel, J. F.
(2008). Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood
112: 2709-2712
[Abstract][Full Text]
Nilsson, S. K., Christensen, S., Raarup, M. K., Ryan, R. O., Nielsen, M. S., Olivecrona, G.
(2008). Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families. J. Biol. Chem.
283: 25920-25927
[Abstract][Full Text]
van der Net, J. B., Oosterveer, D. M., Versmissen, J., Defesche, J. C., Yazdanpanah, M., Aouizerat, B. E., Steyerberg, E. W., Malloy, M. J., Pullinger, C. R., Kastelein, J. J.P., Kane, J. P., Sijbrands, E. J.G.
(2008). Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia. Eur Heart J
29: 2195-2201
[Abstract][Full Text]
Liew, G., Wang, J. J., Mitchell, P., Wong, T. Y.
(2008). Retinal Vascular Imaging: A New Tool in Microvascular Disease Research. Circ Cardiovasc Imaging
1: 156-161
[Abstract][Full Text]
Samani, N. J., Raitakari, O. T., Sipila, K., Tobin, M. D., Schunkert, H., Juonala, M., Braund, P. S., Erdmann, J., Viikari, J., Moilanen, L., Taittonen, L., Jula, A., Jokinen, E., Laitinen, T., Hutri-Kahonen, N., Nieminen, M. S., Kesaniemi, Y. A., Hall, A. S., Hulkkonen, J., Kahonen, M., Lehtimaki, T.
(2008). Coronary Artery Disease-Associated Locus on Chromosome 9p21 and Early Markers of Atherosclerosis. Arterioscler. Thromb. Vasc. Bio.
28: 1679-1683
[Abstract][Full Text]
Dalmasso, C., Genin, E., Tregouet, D.-A.
(2008). A Weighted-Holm Procedure Accounting for Allele Frequencies in Genomewide Association Studies. Genetics
180: 697-702
[Abstract][Full Text]
Burton, P. R, Hansell, A. L, Fortier, I., Manolio, T. A, Khoury, M. J, Little, J., Elliott, P.
(2008). Size matters: just how big is BIG?: Quantifying realistic sample size requirements for human genome epidemiology. Int J Epidemiol
0: dyn147v2-dyn147
[Abstract][Full Text]
Assimes, T. L., Knowles, J. W., Basu, A., Iribarren, C., Southwick, A., Tang, H., Absher, D., Li, J., Fair, J. M., Rubin, G. D., Sidney, S., Fortmann, S. P., Go, A. S., Hlatky, M. A., Myers, R. M., Risch, N., Quertermous, T.
(2008). Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Hum Mol Genet
17: 2320-2328
[Abstract][Full Text]
Ng, M. C.Y., Park, K. S., Oh, B., Tam, C. H.T., Cho, Y. M., Shin, H. D., Lam, V. K.L., Ma, R. C.W., So, W. Y., Cho, Y. S., Kim, H.-L., Lee, H. K., Chan, J. C.N., Cho, N. H.
(2008). Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians. Diabetes
57: 2226-2233
[Abstract][Full Text]
Ye, S., Willeit, J., Kronenberg, F., Xu, Q., Kiechl, S.
(2008). Association of Genetic Variation on Chromosome 9p21 With Susceptibility and Progression of Atherosclerosis: A Population-Based, Prospective Study. J Am Coll Cardiol
52: 378-384
[Abstract][Full Text]
Murray, S. S., Topol, E. J.
(2008). Gaining Insights in Coronary Disease Genomics. J Am Coll Cardiol
52: 385-386
[Full Text]
Samuel, J.-L., Schaub, M. C., Zaugg, M., Mamas, M., Dunn, W. B., Swynghedauw, B.
(2008). Genomics in cardiac metabolism. Cardiovasc Res
79: 218-227
[Abstract][Full Text]
Lewis, G. D., Asnani, A., Gerszten, R. E.
(2008). Application of Metabolomics to Cardiovascular Biomarker and Pathway Discovery. J Am Coll Cardiol
52: 117-123
[Abstract][Full Text]
Grant, S. F. A., Hakonarson, H.
(2008). Microarray Technology and Applications in the Arena of Genome-Wide Association. Clin. Chem.
54: 1116-1124
[Abstract][Full Text]
Thompson, A., Di Angelantonio, E., Sarwar, N., Erqou, S., Saleheen, D., Dullaart, R. P. F., Keavney, B., Ye, Z., Danesh, J.
(2008). Association of Cholesteryl Ester Transfer Protein Genotypes With CETP Mass and Activity, Lipid Levels, and Coronary Risk. JAMA
299: 2777-2788
[Abstract][Full Text]
Tobin, M. D., Tomaszewski, M., Braund, P. S., Hajat, C., Raleigh, S. M., Palmer, T. M., Caulfield, M., Burton, P. R., Samani, N. J.
(2008). Common Variants in Genes Underlying Monogenic Hypertension and Hypotension and Blood Pressure in the General Population. Hypertension
51: 1658-1664
[Abstract][Full Text]
Braunwald, E.
(2008). The Management of Heart Failure: The Past, the Present, and the Future. Circ Heart Fail
1: 58-62
[Full Text]
Sutton, B. S., Crosslin, D. R., Shah, S. H., Nelson, S. C., Bassil, A., Hale, A. B., Haynes, C., Goldschmidt-Clermont, P. J., Vance, J. M., Seo, D., Kraus, W. E., Gregory, S. G., Hauser, E. R.
(2008). Comprehensive genetic analysis of the platelet activating factor acetylhydrolase (PLA2G7) gene and cardiovascular disease in case-control and family datasets. Hum Mol Genet
17: 1318-1328
[Abstract][Full Text]
Malarstig, A., Sigurdsson, S., Eriksson, P., Paulsson-Berne, G., Hedin, U., Wallentin, L., Siegbahn, A., Hamsten, A., Syvanen, A.-C.
(2008). Variants of the Interferon Regulatory Factor 5 Gene Regulate Expression of IRF5 mRNA in Atherosclerotic Tissue But Are Not Associated With Myocardial Infarction. Arterioscler. Thromb. Vasc. Bio.
28: 975-982
[Abstract][Full Text]
Liu, X.-Q., Paterson, A. D., He, N., St. George-Hyslop, P., Rauta, V., Gronhagen-Riska, C., Laakso, M., Thibaudin, L., Berthoux, F., Cattran, D., Pei, Y.
(2008). IL5RA and TNFRSF6B Gene Variants Are Associated With Sporadic IgA Nephropathy. J. Am. Soc. Nephrol.
19: 1025-1033
[Abstract][Full Text]
Matarin, M., Brown, W. M., Singleton, A., Hardy, J. A., Meschia, J. F., for the ISGS investigators,
(2008). Whole Genome Analyses Suggest Ischemic Stroke and Heart Disease Share an Association With Polymorphisms on Chromosome 9p21. Stroke
39: 1586-1589
[Abstract][Full Text]
Trichopoulou, A., Yiannakouris, N., Bamia, C., Benetou, V., Trichopoulos, D., Ordovas, J. M.
(2008). Genetic Predisposition, Nongenetic Risk Factors, and Coronary Infarct. Arch Intern Med
168: 891-896
[Abstract][Full Text]
Koch, W., Hoppmann, P., Biele, J., Mueller, J. C., Schomig, A., Kastrati, A.
(2008). Fibrinogen Genes and Myocardial Infarction: A Haplotype Analysis. Arterioscler. Thromb. Vasc. Bio.
28: 758-763
[Abstract][Full Text]
Yamada, Y, Kato, K, Oguri, M, Fujimaki, T, Yokoi, K, Matsuo, H, Watanabe, S, Metoki, N, Yoshida, H, Satoh, K, Ichihara, S, Aoyagi, Y, Yasunaga, A, Park, H, Tanaka, M, Nozawa, Y
(2008). Genetic risk for myocardial infarction determined by polymorphisms of candidate genes in a Japanese population. J. Med. Genet.
45: 216-221
[Abstract][Full Text]
Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., Orho-Melander, M.
(2008). Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events. NEJM
358: 1240-1249
[Abstract][Full Text]
Bhattacharyya, T., Nicholls, S. J., Topol, E. J., Zhang, R., Yang, X., Schmitt, D., Fu, X., Shao, M., Brennan, D. M., Ellis, S. G., Brennan, M.-L., Allayee, H., Lusis, A. J., Hazen, S. L.
(2008). Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk. JAMA
299: 1265-1276
[Abstract][Full Text]
Pearson, T. A., Manolio, T. A.
(2008). How to Interpret a Genome-wide Association Study. JAMA
299: 1335-1344
[Abstract][Full Text]
Sanz, J., Moreno, P. R., Fuster, V.
(2008). The year in atherothrombosis.. J Am Coll Cardiol
51: 944-955
[Full Text]
Fischer, M., Schunkert, H.
(2008). Familial aggregation of left main coronary artery disease and future risk of coronary events in asymptomatic siblings of affected patients: reply. Eur Heart J
29: 827-828
[Full Text]
Emmerich, J., Ridker, P. M
(2008). Can Fishing for New Genes Catch Patients at Risk of Coronary Artery Disease?. Clin. Chem.
54: 453-455
[Full Text]
Sabatine, M. S., Ploughman, L., Simonsen, K. L., Iakoubova, O. A., Kirchgessner, T. G., Ranade, K., Tsuchihashi, Z., Zerba, K. E., Long, D. U., Tong, C. H., Packard, C. J., Pfeffer, M. A., Devlin, J. J., Shepherd, J., Campos, H., Sacks, F. M., Braunwald, E.
(2008). Association Between ADAMTS1 Matrix Metalloproteinase Gene Variation, Coronary Heart Disease, and Benefit of Statin Therapy. Arterioscler. Thromb. Vasc. Bio.
28: 562-567
[Abstract][Full Text]
Talmud, P. J., Cooper, J. A., Palmen, J., Lovering, R., Drenos, F., Hingorani, A. D., Humphries, S. E.
(2008). Chromosome 9p21.3 Coronary Heart Disease Locus Genotype and Prospective Risk of CHD in Healthy Middle-Aged Men. Clin. Chem.
54: 467-474
[Abstract][Full Text]
Shen, G.-Q., Li, L., Rao, S., Abdullah, K. G., Ban, J. M., Lee, B.-S., Park, J. E., Wang, Q. K.
(2008). Four SNPs on Chromosome 9p21 in a South Korean Population Implicate a Genetic Locus That Confers High Cross-Race Risk for Development of Coronary Artery Disease. Arterioscler. Thromb. Vasc. Bio.
28: 360-365
[Abstract][Full Text]
Frayling, T. M
(2008). Commentary: Genetic association studies see light at the end of the tunnel. Int J Epidemiol
37: 133-135
[Full Text]
Ridker, P. M, Chasman, D. I., Zee, R. Y.L., Parker, A., Rose, L., Cook, N. R., Buring, J. E, for the Women's Genome Health Study Working Group,
(2008). Rationale, Design, and Methodology of the Women's Genome Health Study: A Genome-Wide Association Study of More Than 25 000 Initially Healthy American Women. Clin. Chem.
54: 249-255
[Abstract][Full Text]
Hegele, R. A., Dichgans, M.
(2008). Update on the Genetics of Stroke and Cerebrovascular Disease 2007. Stroke
39: 252-254
[Full Text]
Marian, A. J.
(2008). Surprises of the genome and "personalized" medicine.. J Am Coll Cardiol
51: 456-458
[Full Text]
Cambien, F., Tiret, L.
(2007). Genetics of Cardiovascular Diseases: From Single Mutations to the Whole Genome. Circulation
116: 1714-1724
[Full Text]
Rosenzweig, A.
(2007). Scanning the Genome for Coronary Risk. NEJM
357: 497-499
[Full Text]
Drazen, J. M., Phimister, E. G.
(2007). Publishing Genomewide Association Studies. NEJM
357: 496-496
[Full Text]
