title: Genetic Architecture of Lacunar Stroke.
abstract: OBJECTIVE
  Lacunar strokes comprise ≈20% of all strokes. Despite this frequency, their pathogenesis is poorly understood. Previous genome-wide association studies in lacunar stroke have been disappointing, which may be because of phenotypic heterogeneity. Pathological and radiological studies suggest that there may be different pathologies underlying lacunar strokes. This has led to the suggestion of 2 subtypes: isolated lacunar infarcts and multiple lacunar infarcts and leukoaraiosis.
  
  
  METHODS
  We performed genome-wide analyses in a magnetic resonance imaging-verified cohort of 1012 younger onset lacunar stroke cases and 964 controls. Using these data, we first estimated the heritability of lacunar stroke and its 2 hypothesized subtypes, and secondly, we determined whether this is enriched for regulatory regions in the genome, as defined by data from Encyclopedia of DNA Elements (ENCODE) and other sources. Finally, we determine the evidence for a polygenic contribution from rare variation to lacunar stroke and its subtypes.
  
  
  RESULTS
  Our results indicate a substantial heritable component to magnetic resonance imaging-verified lacunar stroke (20%-25%) and its 2 subtypes (isolated lacunar infarct, 15%-18%; multiple lacunar infarcts/leukoaraiosis, 23%-28%). This heritable component is significantly enriched for sites affecting expression of genes. In addition, we show that the risk of the 2 subtypes of lacunar stroke in isolation, but not in combination, is associated with rare variation in the genome.
  
  
  CONCLUSIONS
  Lacunar stroke, when defined on magnetic resonance imaging, is a highly heritable complex disease. Much of this heritability arises from regions of the genome affecting gene regulation. Rare variation affects 2 subtypes of lacunar in isolation, suggesting that they may have distinct genetic susceptibility factors.
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., S.B., H.S.M.); Department of Neurology, Université Paris Descartes Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale S894, Centre Hospitalier Sainte-Anne, Paris, France (J.-C.B.); Department of Neurology, Leeds General Infirmary, Leeds, United Kingdom (A.H.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (C.M.L.); and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom (C.M.L.). 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., S.B., H.S.M.); Department of Neurology, Université Paris Descartes Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale S894, Centre Hospitalier Sainte-Anne, Paris, France (J.-C.B.); Department of Neurology, Leeds General Infirmary, Leeds, United Kingdom (A.H.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (C.M.L.); and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom (C.M.L.).
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., S.B., H.S.M.); Department of Neurology, Université Paris Descartes Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale S894, Centre Hospitalier Sainte-Anne, Paris, France (J.-C.B.); Department of Neurology, Leeds General Infirmary, Leeds, United Kingdom (A.H.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (C.M.L.); and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom (C.M.L.).
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Baron
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., S.B., H.S.M.); Department of Neurology, Université Paris Descartes Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale S894, Centre Hospitalier Sainte-Anne, Paris, France (J.-C.B.); Department of Neurology, Leeds General Infirmary, Leeds, United Kingdom (A.H.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (C.M.L.); and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom (C.M.L.).
authors.forename: Ahamad
authors.initials: A
authors.lastname: Hassan
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., S.B., H.S.M.); Department of Neurology, Université Paris Descartes Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale S894, Centre Hospitalier Sainte-Anne, Paris, France (J.-C.B.); Department of Neurology, Leeds General Infirmary, Leeds, United Kingdom (A.H.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (C.M.L.); and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom (C.M.L.).
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (M.T., S.B., H.S.M.); Department of Neurology, Université Paris Descartes Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale S894, Centre Hospitalier Sainte-Anne, Paris, France (J.-C.B.); Department of Neurology, Leeds General Infirmary, Leeds, United Kingdom (A.H.); Department of Medical and Molecular Genetics, King's College London, London, United Kingdom (C.M.L.); and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom (C.M.L.).
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
mesh_terms: D000368:Aged; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D059409:Stroke, Lacunar / Q000145:classification / Q000235:genetics*
keywords: genetic association studies; genetics; magnetic resonance imaging; polymorphism, single nucleotide; stroke, lacunar