title: Genetic Associations With White Matter Hyperintensities Confer Risk of Lacunar Stroke.
abstract: White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis.
  
  
  
  We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging-confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups.
  
  
  
  The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI]]=1.14 [1.06-1.22]; P=0.0003), in patients both with and without WMH (WMH: OR [95% CI]=1.15 [1.05-1.26]; P=0.003 and no WMH: OR [95% CI]=1.11 [1.02-1.21]; P=0.019). Conversely, the risk score was not associated with cardioembolic stroke (OR [95% CI]=1.03 [0.97-1.09]; P=0.63) or large vessel stroke (OR [95% CI]=0.99 [0.93,1.04]; P=0.39). However, none of the WMH-associated single nucleotide polymorphisms passed Bonferroni-corrected significance for association with lacunar stroke.
  
  
  
  Genetic variants that influence WMH are associated with an increased risk of lacunar stroke but not cardioembolic or large vessel stroke. Some genetic susceptibility factors seem to be shared across different radiological manifestations of small vessel disease.
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.). mt628@medschl.cam.ac.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Traylor
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Loes C A
authors.initials: LC
authors.lastname: Rutten-Jacobs
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Thijs
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Chris
authors.initials: C
authors.lastname: Levi
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Steve
authors.initials: S
authors.lastname: Bevan
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Rainer
authors.initials: R
authors.lastname: Malik
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Giorgio
authors.initials: G
authors.lastname: Boncoraglio
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Cathie
authors.initials: C
authors.lastname: Sudlow
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Peter M
authors.initials: PM
authors.lastname: Rothwell
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., L.C.A.R.-J., H.S.M.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (M.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.); School of Medicine and Public Health (E.G.H.) and Centre for Clinical Epidemiology and Biostatistics, Hunter Medical Research Institute and School of Medicine and Public Health (C.L.), University of Newcastle, Newcastle, NSW, Australia; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia (E.G.H.); School of Life Science, University of Lincoln, Lincoln, United Kingdom (S.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Department of Cerebrovascular Disease, IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (G.B.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.).
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D049292:Leukoaraiosis / Q000000981:diagnostic imaging* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D012306:Risk; D059409:Stroke, Lacunar / Q000000981:diagnostic imaging* / Q000235:genetics*
keywords: cerebral small vessel diseases; genetic association studies; genetics; leukoencephalopathies; stroke, lacunar