Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.
International Stroke Genetics Consortium (ISGC) None., Wellcome Trust Case Control Consortium 2 (WTCCC2) None., Bellenguez C., Bevan S., Gschwendtner A., Spencer CCA., Burgess AI., Pirinen M., Jackson CA., Traylor M., Strange A., Su Z., Band G., Syme PD., Malik R., Pera J., Norrving B., Lemmens R., Freeman C., Schanz R., James T., Poole D., Murphy L., Segal H., Cortellini L., Cheng Y-C., Woo D., Nalls MA., Müller-Myhsok B., Meisinger C., Seedorf U., Ross-Adams H., Boonen S., Wloch-Kopec D., Valant V., Slark J., Furie K., Delavaran H., Langford C., Deloukas P., Edkins S., Hunt S., Gray E., Dronov S., Peltonen L., Gretarsdottir S., Thorleifsson G., Thorsteinsdottir U., Stefansson K., Boncoraglio GB., Parati EA., Attia J., Holliday E., Levi C., Franzosi M-G., Goel A., Helgadottir A., Blackwell JM., Bramon E., Brown MA., Casas JP., Corvin A., Duncanson A., Jankowski J., Mathew CG., Palmer CNA., Plomin R., Rautanen A., Sawcer SJ., Trembath RC., Viswanathan AC., Wood NW., Worrall BB., Kittner SJ., Mitchell BD., Kissela B., Meschia JF., Thijs V., Lindgren A., Macleod MJ., Slowik A., Walters M., Rosand J., Sharma P., Farrall M., Sudlow CLM., Rothwell PM., Dichgans M., Donnelly P., Markus HS.
Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.