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BACKGROUND AND PURPOSE:Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. METHODS:Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. RESULTS:Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)). CONCLUSIONS:Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

Original publication

DOI

10.1161/strokeaha.113.002707

Type

Journal article

Journal

Stroke

Publication Date

01/2014

Volume

45

Pages

24 - 36

Addresses

From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany (M.D., R. Malik); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Institut für Medizinische Biometrie und Statistik (I.R.K.), and Institut für integrative und experimentelle Genomik (J.E.), Universität zu Lübeck, Lübeck, Germany; Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Germany (I.R.K.); Department of Neurology and Center for Human Genetic Research (J.R.), and Cardiology Division (C.J.O.D.), Massachusetts General Hospital, Boston; Harvard Medical School, Boston, MA (J.R.); Program in Medical and Population Genetics (J.R.), and Program in Medical and Population Genetics (S.K.), Broad Institute of Harvard and MIT, Cambridge, MA; Clinical Trial Service Unit and Epidemiological Studies Unit (R.C., J.C.H.), Wellcome Trust Centre for Human Genetics (H.W., M. Farrall), Department of Cardiovascular Medicine (M. Farrall), and Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience (P.M.R.), John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; deCODE Genetics, Reykjavik, Iceland (S.G., G.T., U.T., K.S.); Department of Medicine, University of Maryland School of Medicine, Baltimore (B.D.M.); Department of Medicine, Stanford University School of Medicine, Stanford, CA (T.L.A.); Center for Translational Neuroscience and Mental Health Research, University of Newcastle, New South Wales, Australia (C.L.); Hunter Medical Research Institute, New South Wales, Australia (C.L.); National Heart, Lung and Blood Institute and NHLBI's Framingham Heart Study, MA (C.J.O.D., S.S.); University of Texas Health Science Center at Houston (M. Fornage); Cardiovascular Health Research Unit, Department of Epidemiology (B.M.P.), Department of Medicine (B.M.P.), Department of Health Services (B.M.P.), and Cardiovascular Health Research Unit, Department of Medicine (J.C.B.), University

Keywords

METASTROKE Consortium, CARDIoGRAM Consortium, C4D Consortium, International Stroke Genetics Consortium, Humans, Brain Ischemia, Genetic Predisposition to Disease, Data Interpretation, Statistical, Risk Factors, Reproducibility of Results, Phenotype, Polymorphism, Single Nucleotide, Coronary Artery Disease, Stroke, Genome-Wide Association Study