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    Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

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    Author
    Traylor, M.
    Anderson, C.D.
    Mitchell, B.D.
    Date
    2019
    Journal
    Circulation. Genomic and precision medicine
    Publisher
    American Heart Association
    Type
    Article
    
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    See at
    https://www.doi.org/10.1161/CIRCGEN.118.002338
    Abstract
    BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16?664 stroke cases and 32?792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.
    Keyword
    atherosclerosis
    cerebral hemorrhage
    chromosome
    dementia
    haplotype
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069935768&doi=10.1161%2fCIRCGEN.118.002338&partnerID=40&md5=4a154009574d2ef796de67cb65c33978; http://hdl.handle.net/10713/10339
    ae974a485f413a2113503eed53cd6c53
    10.1161/CIRCGEN.118.002338
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