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The aim of this doctoral thesis was to investigate the genetic variation underlying ischaemic stroke and its subtypes, and to determine how this genetic variation is related to other diseases such as Alzheimer's Disease. First, a genome wide meta-analysis was performed as part of the METASTROKE collaboration (12,389 cases, 62,004 controls) to validate existing associations with ischaemic stroke, and to attempt to identify novel associations. Four existing associations were validated, however no novel associations could be identified. Secondly, a number of approaches were taken to evaluate the hypothesis that early onset cases of ischaemic stroke subtypes have a stronger genetic predisposition. All known associations with ischaemic stroke subtypes were found to have stronger effects in younger onset cases, evidence was found genomewide of stronger effects in younger onset cases, and younger onset cases were found to have higher heritability. Thirdly, a covariate-informed approach to genetic association analysis was investigated to determine if such an approach has more power than conventional approaches to detect associations with ischaemic stroke and its subtypes. An age-at-onset informed approach was found to have more power than standard analysis. The approach was used to identify a novel association of an MMP12 locus with large vessel disease stroke, which was found to be overexpressed in carotid plaques compared to controls. Finally, a genetic risk score approach was used to evaluate the shared genetic contribution to ischaemic stroke and Alzheimer's Disease. A significant genetic correlation between the two diseases was identified and the association was considerably stronger for the small vessel subtype of ischaemic stroke. |
