Steven A Lubitz1, Owen E Parsons2, Christopher D Anderson2, Emelia J Benjamin2, Rainer Malik2, Lu-Chen Weng2, Martin Dichgans2, Cathie L Sudlow2, Peter M Rothwell2, Jonathan Rosand2, Patrick T Ellinor2, Hugh S Markus2, Matthew Traylor2. 1. From the Stroke Research Center (C.D.A., J.R.), Center for Human Genetic Research (C.D.A., J.R.), and Cardiovascular Research Center (S.A.L., L.-C.W., P.T.E.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, The Broad Insitute of Harvard and MIT, Cambridge, MA (S.A.L., L.-C.W., C.D.A., J.R., P.T.E.); Autism Research Centre (O.E.P.) and Department of Clinical Neurosciences (H.S.M., M.T.), University of Cambridge, United Kingdom; Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, MA (E.J.B.); Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, MA (E.J.B.); Department of Epidemiology, Boston University School of Public Health, MA (E.J.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians Universität, Germany (R.M., M.D.); Munich Cluster of Systems Neurology (SyNergy), Germany (M.D.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom (C.L.S.); and Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, United Kingdom (P.M.R.). slubitz@mgh.harvard.edu. 2. From the Stroke Research Center (C.D.A., J.R.), Center for Human Genetic Research (C.D.A., J.R.), and Cardiovascular Research Center (S.A.L., L.-C.W., P.T.E.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, The Broad Insitute of Harvard and MIT, Cambridge, MA (S.A.L., L.-C.W., C.D.A., J.R., P.T.E.); Autism Research Centre (O.E.P.) and Department of Clinical Neurosciences (H.S.M., M.T.), University of Cambridge, United Kingdom; Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, MA (E.J.B.); Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, MA (E.J.B.); Department of Epidemiology, Boston University School of Public Health, MA (E.J.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians Universität, Germany (R.M., M.D.); Munich Cluster of Systems Neurology (SyNergy), Germany (M.D.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom (C.L.S.); and Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, United Kingdom (P.M.R.).
Abstract
BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. METHODS: We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. RESULTS: There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association (P=6×10-4) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P<1×10-3 in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest P=1.2×10-9, 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. CONCLUSIONS: Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses.
BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. METHODS: We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. RESULTS: There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association (P=6×10-4) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P<1×10-3 in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest P=1.2×10-9, 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. CONCLUSIONS: Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses.
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