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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Abstract

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.

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Figure 1: Genome-wide association results at autosomal SNPs in combined UK and German discovery samples.
Figure 2: Forest plot for the associations between rs11984041 and large vessel stroke in discovery and replication collections.
Figure 3: Genetic heterogeneity of different stroke subtypes for the four loci with significant associations.
Figure 4: Plot of association signals around rs11984041 for large vessel stroke in the combined UK and German discovery samples.

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Acknowledgements

We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, M.L. Perez, C.R. Stribling, S. Taylor and A. Wilk of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We acknowledge use of the British 1958 Birth Cohort DNA collection, which is funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls funded by the Wellcome Trust. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank the following individuals who contributed to collection, phenotyping, sample processing and data management for the different cohorts: A. Burgess, A. Syed and N. Paul (Oxford Vascular Study); M. Dennis, P. Sandercock, C. Warlow, S. Hart, S. Keir, J. Wardlaw, A. Farrall, G. Potter, A. Hutchison and M. McDowall (Edinburgh Stroke Study); A. Pasdar and H. Clinkscale (Aberdeen); P. Higgins (Glasgow); T.G. Brott, R.D. Brown, S. Silliman, M. Frankel, D. Case, S. Rich, J. Hardy, A. Singleton (ISGS); M.J. Sparks, K. Ryan, J. Cole, M. Wozniak, B. Stern, R. Wityk, C. Johnson and D. Buchholz (GEOS); and J. Maguire, S. Koblar, J. Golledge, J. Surm, G. Hankey, J. Jannes, M. Lewis, R. Scott, L. Lincz; P. Moscato and R. Baker (Australian Stroke Genetics Collaborative membership). The principal funding for this study was provided by the Wellcome Trust as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). For details of other funding support, see the Supplementary Note.

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S. Bevan, C.C.A.S., P.S., M.F., C.L.M.S., P.M.R., M.D., P. Donnelly and H.S.M. designed the experiment. S. Bevan, A.G., A.I.B., C.A.J., T.J., D.P., L.M., H.S., C.L.M.S., P.M.R., M.D. and H.S.M. were responsible for collecting and phenotyping discovery samples. Replication sample or replication data were provided by P.D.S., J.P., B.N., R.L., R.S., L.C., Y.-C.C., D.W., M.A.N., U.S., H.R.-A., S. Boonen, D.W.-K., V.V., J.S., K.F., H.D., S.G., G.T., U.T., K.S., G.B.B., E.A.P., J.A., E.H., C.L., M.-G.F., A.H., B.B.W., S.J.K., B.D.M., B.K., J.F.M., V.T., A.L., M.J.M., A.S., M.W., J.R. and P.S. Genotyping, quality control and informatics were conducted by C.B., S. Bevan, C.C.A.S., M.P., M.T., A.S., Z.S., G.B., C.F., R.M., B.M.-M., C.M., C.L., S.E., S.H., E.G., S.D., A.G., M.F., P. Donnelly and H.S.M. Genetic and statistical analysis was performed by C.B., S.B., C.C.A.S., M.P., A.S., Z.S., G.B., C.F., M.T., R.M., A.H., M.F. and P. Donnelly. The WTCCC2 management committee (P. Donnelly (Chair), L.P. (Deputy Chair), J.M.B., E.B., M.A.B., J.P.C., A.C., P. Deloukas, A.D., J.J., H.S.M., C.G.M., C.N.A.P., R.P., A.R., S.J.S., R.C.T., A.C.V. and N.W.W.) monitored the execution of the study. C.B., S. Bevan, C.C.A.S., M.P., M.F., P. Donnelly and H.S.M. contributed to writing the first draft of the manuscript. All authors reviewed and commented on the final manuscript.

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Correspondence to Peter Donnelly or Hugh S Markus.

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A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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Supplementary Tables 1–6, Supplementary Figure 1 and Supplementary Note (PDF 295 kb)

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The International Stroke Genetics Consortium (ISGC)., the Wellcome Trust Case Control Consortium 2 (WTCCC2)., Bellenguez, C. et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet 44, 328–333 (2012). https://doi.org/10.1038/ng.1081

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