title: Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.
abstract: OBJECTIVE
  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.
authors.affiliation: 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
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authors.forename: Cathie
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authors.initials: HS
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000150:complications / Q000453:epidemiology; D001794:Blood Pressure / Q000502:physiology; D002545:Brain Ischemia / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000150:complications / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D058885:Multilocus Sequence Typing; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011153:Population; D011446:Prospective Studies; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D020521:Stroke / Q000453:epidemiology* / Q000235:genetics*
keywords: genetics; polymorphism, genetic; risk assessment; risk factors