Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls.
Falcone, Guido J
Comeau, Mary E
Sudlow, Cathie LM
Mitchell, Braxton D
Cole, John W
Grewal, Raji P
Langefeld, Carl D
Kittner, Steven J
NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC),
Circulation. Genomic and precision medicine
American Heart Association
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Traylor, M., Anderson, C. D., Jacobs, L., Falcone, G. J., Comeau, M. E., Ay, H., Sudlow, C. L., et al. (2019). Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls.. Circulation. Genomic and precision medicine, 12 (7), e002338. https://doi.org/10.1161/circgen.118.002338
BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischaemic and haemorrhagic 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 two commonly used stroke classification systems, Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS). All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both haemorrhagic and ischaemic stroke, three of which influenced ischaemic and haemorrhagic subtypes under both TOAST and CCS. Under CCS, 4 loci influenced both small vessel stroke and intracerebral haemorrhage. An EDNRA locus demonstrated opposing effects on ischaemic and haemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction and only one locus (12q24) was predicted to influence all ischaemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between haemorrhagic and ischaemic 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.
NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC), Humans, Bayes Theorem, Case-Control Studies, Genotype, Aged, Aged, 80 and over, Middle Aged, Europe, Female, Male, Stroke, Genome-Wide Association Study, Genetic Loci
This work was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). The National Institute of Neurological Disorders and Stroke – Stroke Genetics Network (NINDS-SIGN) study was funded by the US National Institute of Neurological Disorders and Stroke, National Institutes of Health (U01 NS069208 and R01 NS100178). Collection of the UK Young Lacunar Stroke DNA Study (DNA Lacunar) was primarily supported by the Wellcome Trust (WT072952) with additional support from the Stroke Association (TSA 2010/01). Genotyping of the DNA Lacunar samples was supported by a Stroke Association Grant (TSA 2013/01). The principal funding for the WTCCC2 stroke study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). Hugh Markus is supported by a National Institute for Health Research (NIHR) Senior Investigator award, and his work is supported by the Cambridge Universities NIHR Comprehensive Biomedical Research Centre. Dr. Anderson is supported by NIH R01NS103924 and K23NS086873.
British Heart Foundation (RG/16/4/32218)
External DOI: https://doi.org/10.1161/circgen.118.002338
This record's URL: https://www.repository.cam.ac.uk/handle/1810/294249
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