title: Oxidative phosphorylation and lacunar stroke: Genome-wide enrichment analysis of common variants.
abstract: OBJECTIVE
  We investigated whether oxidative phosphorylation (OXPHOS) abnormalities were associated with lacunar stroke, hypothesizing that these would be more strongly associated in patients with multiple lacunar infarcts and leukoaraiosis (LA).
  
  
  METHODS
  In 1,012 MRI-confirmed lacunar stroke cases and 964 age-matched controls recruited from general practice surgeries, we investigated associations between common genetic variants within the OXPHOS pathway and lacunar stroke using a permutation-based enrichment approach. Cases were phenotyped using MRI into those with multiple infarcts or LA (MLI/LA) and those with isolated lacunar infarcts (ILI) based on the number of subcortical infarcts and degree of LA, using the Fazekas grading. Using gene-level association statistics, we tested for enrichment of genes in the OXPHOS pathway with all lacunar stroke and the 2 subtypes.
  
  
  RESULTS
  There was a specific association with strong evidence of enrichment in the top 1% of genes in the MLI/LA (subtype p = 0.0017) but not in the ILI subtype (p = 1). Genes in the top percentile for the all lacunar stroke analysis were not significantly enriched (p = 0.07).
  
  
  CONCLUSIONS
  Our results implicate the OXPHOS pathway in the pathogenesis of lacunar stroke, and show the association is specific to patients with the MLI/LA subtype. They show that MRI-based subtyping of lacunar stroke can provide insights into disease pathophysiology, and imply that different radiologic subtypes of lacunar stroke subtypes have distinct underlying pathophysiologic processes.
authors.affiliation: From Clinical Neurosciences (M.T., R.H., H.S.M.), University of Cambridge, UK; School of Life Science (S.B.), University of Lincoln, UK; and the Center for Human Genetic Research (C.D.A.), Department of Neurology, Massachusetts General Hospital, Boston. mt628@medschl.cam.ac.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Traylor
authors.affiliation: From Clinical Neurosciences (M.T., R.H., H.S.M.), University of Cambridge, UK; School of Life Science (S.B.), University of Lincoln, UK; and the Center for Human Genetic Research (C.D.A.), Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.affiliation: From Clinical Neurosciences (M.T., R.H., H.S.M.), University of Cambridge, UK; School of Life Science (S.B.), University of Lincoln, UK; and the Center for Human Genetic Research (C.D.A.), Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: Robert
authors.initials: R
authors.lastname: Hurford
authors.affiliation: From Clinical Neurosciences (M.T., R.H., H.S.M.), University of Cambridge, UK; School of Life Science (S.B.), University of Lincoln, UK; and the Center for Human Genetic Research (C.D.A.), Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: Steve
authors.initials: S
authors.lastname: Bevan
authors.affiliation: From Clinical Neurosciences (M.T., R.H., H.S.M.), University of Cambridge, UK; School of Life Science (S.B.), University of Lincoln, UK; and the Center for Human Genetic Research (C.D.A.), Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
mesh_terms: D000328:Adult; D000368:Aged; D002544:Cerebral Infarction / Q000150:complications / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D049292:Leukoaraiosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010085:Oxidative Phosphorylation; D012307:Risk Factors; D059409:Stroke, Lacunar / Q000150:complications / Q000235:genetics*; D055815:Young Adult