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BACKGROUND AND PURPOSE:Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. METHODS:Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. RESULTS:High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene. CONCLUSIONS:Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

Original publication

DOI

10.1161/strokeaha.114.007930

Type

Journal article

Journal

Stroke

Publication Date

03/2015

Volume

46

Pages

615 - 619

Addresses

From the School of Medicine and Public Health (E.G.H., J.A.), School of Biomedical Sciences and Pharmacy (L.F.L., R.J.S.), and School of Nursing and Midwifery (J.M.M.), University of Newcastle, Australia; Clinical Research Design, IT and Statistical Support Unit, Public Health Research Program, Hunter Medical Research Institute, Newcastle, Australia (E.G.H., C.O., J.A.); Department of Clinical Neurosciences, University of Cambridge, UK (M.T., S.B., H.S.M.); Institute for Stroke and Dementia Research, Klinikum der Universität Mün-chen, Ludwig-Maximilians-Universität, Munich, Germany (R.M., M.D.); Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA (G.F., J.R.); Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA (G.F., J.R.); Clinical Trial Service Unit and Epidemiological Studies Unit (J.C.H., R.C.) and Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience (P.M.R.), University of Oxford, UK; Department of Medicine (Y.-C.C., B.D.M.) and Department of Neurology (J.W.C., S.J.K.), University of Maryland School of Medicine, Baltimore, MD; Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College, London, UK (I.C.); Cardiovascular Health Research Unit, Department of Medicine (J.C.B., B.M.P., K.L.W.) and Department of Epidemiology (B.M.P.), University of Washington, Seattle, WA; Institute of Molecular Medicine and Human Genetics Center, the University of Texas Health Science Center at Houston, TX (E.B., M.F.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.B., E.A.P.); Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD (J.W.C., S.J.K.); Department of Neurology, Rhode Island Hospital, Providence, RI (K.L.F.); Departments of Epidemiology, Neurology, and Radiology, Erasmus University Medical Center, Rotterdam, the Netherlands (M.A.I.); School of Medicine, University of Adelaide, Australia (J.J.); H

Keywords

Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2, International Stroke Genetics Consortium, Humans, Embolism, Ischemia, Data Interpretation, Statistical, Linear Models, Cohort Studies, Genotype, Phenotype, Polymorphism, Single Nucleotide, Alleles, Atherosclerosis, Meta-Analysis as Topic, Stroke, Genome-Wide Association Study, Cerebral Small Vessel Diseases