The Genetic Architecture of Lacunar Stroke
MetadataShow full item record
Traylor, M., Bevan, S., Baron, J., Hassan, A., Lewis, C., & Markus, H. (2015). The Genetic Architecture of Lacunar Stroke. Stroke https://doi.org/10.1161/STROKEAHA.115.009485
Background and Purpose Lacunar strokes comprise approximately 20% of all strokes. Despite this frequency, their pathogenesis is poorly understood. Previous GWA studies in lacunar stroke have been disappointing, which may be due to phenotypic heterogeneity. Pathological and radiological studies suggest there may be different pathologies underlying lacunar stroke. This has led to the suggestion of two subtypes: isolated lacunar infarcts (ILI) and multiple infarcts and leukoaraiosis (MLI/LA). Methods We performed genome wide analyses in an MRI-verified cohort of 1,012 younger onset lacunar stroke cases and 964 controls. Using this data we first estimated the heritability of lacunar stroke and the two hypothesized subtypes, and secondly determined whether this is enriched for regulatory regions in the genome, as defined by data from 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 MRI verified lacunar stroke (20-25%) and its two subtypes (ILI, 15-18%; MLI / LA, 23-28%). This heritable component is significantly enriched for sites affecting expression of genes. Additionally, we show that risk of the two subtypes of lacunar stroke in isolation, but not in combination, is associated with rare variation in the genome. Conclusions Lacunar stroke, when defined on MRI, is a highly heritable complex disease. Much of this heritability arises from regions of the genome affecting gene regulation. Rare variation impacts on two subtypes of lacunar in isolation, suggesting that they may have distinct genetic susceptibility factors.
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 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).
External DOI: https://doi.org/10.1161/STROKEAHA.115.009485
This record's URL: https://www.repository.cam.ac.uk/handle/1810/249033
Creative Commons Attribution-NonCommercial 4.0
Licence URL: http://creativecommons.org/licenses/by-nc/4.0/