Genetic overlap between diagnostic subtypes of ischemic stroke

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dc.contributor.authorHolliday, E.
dc.contributor.authorTraylor, M.
dc.contributor.authorMalik, R.
dc.contributor.authorBevan, S.
dc.contributor.authorFalcone, G.
dc.contributor.authorHopewell, J.
dc.contributor.authorCheng, Y.
dc.contributor.authorCotlarciuc, I.
dc.contributor.authorBis, J.
dc.contributor.authorBoerwinkle, E.
dc.contributor.authorBoncoraglio, G.
dc.contributor.authorClarke, R.
dc.contributor.authorCole, J.
dc.contributor.authorFornage, M.
dc.contributor.authorFurie, K.
dc.contributor.authorIkram, M.
dc.contributor.authorJannes, J.
dc.contributor.authorKittner, S.
dc.contributor.authorLincz, L.
dc.contributor.authorMaguire, J.
dc.contributor.authoret al.
dc.date.issued2015
dc.description.abstractBACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene. CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
dc.description.statementofresponsibilityElizabeth G. Holliday ... Jim Jannes ... et al. on behalf of the Australian Stroke Genetics Collaborative, the Wellcome Trust Case Control Consortium 2, and the International Stroke Genetics Consortium
dc.identifier.citationStroke, 2015; 46(3):615-619
dc.identifier.doi10.1161/STROKEAHA.114.007930
dc.identifier.issn0039-2499
dc.identifier.issn1524-4628
dc.identifier.orcidJannes, J. [0000-0003-1440-2572]
dc.identifier.urihttp://hdl.handle.net/2440/92260
dc.language.isoen
dc.publisherAmerican Heart Association
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/613602
dc.rights© 2015 American Heart Association, Inc.
dc.source.urihttps://doi.org/10.1161/strokeaha.114.007930
dc.subjectatherosclerosis
dc.subjectgenetic epidemiology
dc.subjectlacunar stroke
dc.titleGenetic overlap between diagnostic subtypes of ischemic stroke
dc.typeJournal article
pubs.publication-statusPublished

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