Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12.
Kilarski LL., Achterberg S., Devan WJ., Traylor M., Malik R., Lindgren A., Pare G., Sharma P., Slowik A., Thijs V., Walters M., Worrall BB., Sale MM., Algra A., Kappelle LJ., Wijmenga C., Norrving B., Sandling JK., Rönnblom L., Goris A., Franke A., Sudlow C., Rothwell PM., Levi C., Holliday EG., Fornage M., Psaty B., Gretarsdottir S., Thorsteinsdottir U., Seshadri S., Mitchell BD., Kittner S., Clarke R., Hopewell JC., Bis JC., Boncoraglio GB., Meschia J., Ikram MA., Hansen BM., Montaner J., Thorleifsson G., Stefanson K., Rosand J., de Bakker PIW., Farrall M., Dichgans M., Markus HS., Bevan S., GARNET Collaborative Research Group, Wellcome Trust Case Control Consortium 2, Australian Stroke Genetic Collaborative, the METASTROKE Consortium, and the International Stroke Genetics Consortium None.
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.