Abstract
Objectives:To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.Methods:Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico “look-up” of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.Results:In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07–1.13], p = 7.12 × 10−11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90–1.17], p = 0.695).Conclusion:Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
Highlights
The analysis plan for this study was to perform a single meta-analysis of available data as follows: (1) association analysis of imputed Immunochip data; (2) meta-analysis with HAPMAP2imputed Wellcome Trust Case Control Consortium 2 (WTCCC2) data and METASTROKE consortium data for which summary statistics were available; and (3): in silico look-up of significant single nucleotide polymorphisms (SNPs) from meta-analysis in the INTERSTROKE cohort[7] and the Vitamin intervention for stroke prevention (VISP) cohort.[8]
For this analysis the WTCCC2 data were removed from METASTROKE to prevent duplication of individuals, as was the BRAINS dataset, which overlapped with BRAINS cases contributing to the Immunochip discovery cohort
Analysis of the 6 Immunochip cohorts comprising 3,420 cases and 6,821 controls resulted in identification of 3 SNPs spanning 2 independent loci on chromosomes 10q26 and 19q13 exceeding a genome-wide significance threshold of 5 3 1028 for all ischemic stroke, and a further 9 SNPs spanning 5 loci in large artery ischemic stroke
Summary
To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases
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