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BACKGROUND AND PURPOSE:Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. METHODS:Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. RESULTS:A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. CONCLUSIONS:A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

Original publication




Journal article



Publication Date





394 - 402


From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany (R.M., M.D.); Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom (S.B., H.S.M.); Laboratory of Neurogenetics (M.A.N.) and Laboratory of Epidemiology and Population Sciences (L.J.L.), National Institute on Aging, National Institutes of Health, Bethesda, MD; Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health (E.G.H.) and Center for Translational Neuroscience and Mental Health Research (C.L.), University of Newcastle, Callaghan, NSW, Australia; Center for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton, NSW, Australia (E.G.H.); Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA (W.J.D., J.R.); Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (Y.-C.C., B.D.M.); Department of Veterans Affairs and Veterans Affairs Medical Center, Baltimore Geriatric Research, Education, and Clinical Center (GRECC), Baltimore, MD (Y.-C.C., B.D.M.); Department of Epidemiology (C.A.I.-V., B.F.J.V., M.A.I., C.M.v.D.), Department of Neurology (C.A.I.-V., M.A.I.), and Department of Radiology (B.F.J.V., M.A.I.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Cardiovascular Health Research Unit (J.C.B., B.M.P.), Department of Medicine (J.C.B., B.M.P.), Department of Epidemiology (B.M.P.), and Department of Health Services (B.M.P.), University of Washington, Seattle, WA; Institute for Molecular Medicine (A.Y.J., M.F.) and Human Genetics Center (M.F.), University of Texas Health Science Center at Houston; Department of Neurology, Boston University School of Medicine, Boston, MA (A.L.d.S., S.S.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (A.L.d.S.); The National Heart, Lung and


Wellcome Trust Case Control Consortium 2, Humans, Brain Ischemia, Atrial Fibrillation, Hypertension, Genetic Predisposition to Disease, Risk Assessment, Risk Factors, Case-Control Studies, Cohort Studies, Prospective Studies, Reproducibility of Results, Sex Factors, Blood Pressure, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Population, Female, Male, Coronary Artery Disease, Stroke, Genetic Variation, Genome-Wide Association Study, Multilocus Sequence Typing