Abstract
ObjectiveIncreasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases.MethodsUsing genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred.ResultsWe found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response.InterpretationOur findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747
Highlights
Using genome-wide association study (GWAS) data from METASTROKE 1 (15,916 ischemic stroke (IS) cases and 68,826 controls) and the International Genomics of Alzheimer’s Project (IGAP; 17,008 Alzheimer’s disease (AD) cases and 37,154 controls), we evaluated known associations with AD and IS
Analysis of GWAS Significant Loci None of the single-nucleotide polymorphism (SNP) associated with IS were associated with AD (p > 0.1)
None of the SNPs associated with AD passed Bonferroni correction for association with IS or any of the three subtypes
Summary
Study Design and Participating Cohorts Two different sets of cases and controls were used in two different parts of the analysis (Table 1). For the metaanalysis and subsequent pathway analysis (analyses i, iii, and iv), we used data from METASTROKE 1 and the International Genomics of Alzheimer’s Project (IGAP) as follows. The METASTROKE 1 data set consisted of IS cases and controls derived from three previously published populations: METASTROKE,[38] WTCCC2Immunochip,[39] and UK Young Lacunar Stroke DNA resource.[40] All cohorts consisted of IS cases of European ancestry from Europe, North America, and Australia together with controls of matched ancestry. The Heart Protection study (N cases/controls 5 578/468) and Rotterdam (N cases/controls 5 376/5396), TOAST subtyping was not performed. The results of the association analyses from each group (METASTROKE, WTCCC2-Immunochip, and DNA-lacunar)
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