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dc.contributor.authorTraylor, Matthewen
dc.contributor.authorBevan, Stephenen
dc.contributor.authorBaron, Jean-Claudeen
dc.contributor.authorHassan, Ahamaden
dc.contributor.authorLewis, Cathrynen
dc.contributor.authorMarkus, Hughen
dc.date.accessioned2015-07-23T14:40:21Z
dc.date.available2015-07-23T14:40:21Z
dc.date.issued2015-08-04en
dc.identifier.issn0039-2499
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/249033
dc.description.abstractBackground 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.
dc.description.sponsorshipHugh 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).
dc.languageEnglishen
dc.language.isoenen
dc.rightsCreative Commons Attribution-NonCommercial 4.0
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.titleThe Genetic Architecture of Lacunar Strokeen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from the American Heart Association via http://dx.doi.org/10.1161/STROKEAHA.115.009485en
prism.publicationDate2015en
prism.publicationNameStrokeen
dc.rioxxterms.funderNIHR
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderStroke Association
dc.rioxxterms.projectidTSA 2013/01
dcterms.dateAccepted2015-06-19en
rioxxterms.versionofrecord10.1161/STROKEAHA.115.009485en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-08-04en
dc.contributor.orcidTraylor, Matthew [0000-0001-6624-8621]
dc.contributor.orcidBaron, Jean-Claude [0000-0002-5264-2588]
dc.contributor.orcidMarkus, Hugh [0000-0002-9794-5996]
dc.identifier.eissn1524-4628
rioxxterms.typeJournal Article/Reviewen


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