Oxidative Phosphorylation and Lacunar Stroke: Genome-wide Enrichment Analysis of Common Variants

Objectives: 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. Methods: In 1,012 MRI-confirmed lacunar stroke cases and 964 age-matched controls recruited from General pratice 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 leukoaraiosis (MLI/LA) and those with isolated lacunar infarcts (ILI) based on the number of subcortical infarcts and degree of leukoaraiosis, 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 two 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 radiological subtypes of lacunar stroke subtypes have distinct underlying pathophysiological processes.Hugh Markus is supported by an NIHR Senior Investigator award. Hugh Markus and Steve Bevan are supported by the NIHR Cambridge University Hospitals Comprehensive Biomedical Research Centre. Collection of the UK Young Lacunar Stroke Resource was primarily supported by a Functional Genomics grant from the Wellcome Trust with additional support from the Stroke Association. Genotyping and MT were supported by a project grant from the Stroke Association (TSA 2013/01). Dr. Anderson is supported by NIH-NINDS K23 NS086873 and a Fellowship in Therapeutic Investigation sponsored by the Massachusetts General Hospital Department of Neurology and Biogen Idec, Inc.This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/WNL.000000000000226