Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.


  1. Department of Health. Reducing Brain Damage: Faster Access to Better Stroke Care (National Audit Office, London, 2005).

  2. Sacco, R.L. et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann. Neurol. 25, 382–390 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Dichgans, M. Genetics of ischaemic stroke. Lancet Neurol. 6, 149–161 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Jerrard-Dunne, P., Cloud, G., Hassan, A. & Markus, H.S. Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke 34, 1364–1369 (2003).

    Article  PubMed  Google Scholar 

  5. Gretarsdottir, S. et al. Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann. Neurol. 64, 402–409 (2008).

    Article  PubMed  Google Scholar 

  6. Lemmens, R. et al. The association of the 4q25 susceptibility variant for atrial fibrillation with stroke is limited to stroke of cardioembolic etiology. Stroke 41, 1850–1857 (2010).

    Article  PubMed  Google Scholar 

  7. Gschwendtner, A. et al. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann. Neurol. 65, 531–539 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Markus, H.S. Genetics studies in ischaemic stroke. Transl. Stroke Res. 1, 238–245 (2010).

    Article  PubMed  Google Scholar 

  9. Adams, H.P. Jr. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24, 35–41 (1993).

    Article  PubMed  Google Scholar 

  10. Gudbjartsson, D.F. et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat. Genet. 41, 876–878 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. International Stroke Genetics Consortium & Wellcome Trust Case-Control Consortium 2. Failure to validate association between 12p13 variants and ischemic stroke. N. Engl. J. Med. 22, 1547–1550 (2010).

  12. Olsson, S. et al. Genetic variant on chromosome 12p13 does mot show association to ischemic stroke in 3 Swedish case-control studies. Stroke 42, 214–216 (2011).

    Article  PubMed  Google Scholar 

  13. Ikram, M.A. et al. Genomewide association studies of stroke. N. Engl. J. Med. 360, 1718–1728 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen, K. et al. Strong association between the NINJ2 gene polymorphism and the susceptibility of stroke in Chinese Han population in Fangshan district. Beijing Da Xue Xue Bao 42, 498–502 (2010).

    CAS  PubMed  Google Scholar 

  15. Newton-Cheh, C. et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 468, 707–713 (2010).

    Article  Google Scholar 

  17. Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Haberland, M., Montgomery, R.L. & Olson, E.N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10, 32–42 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chang, S. et al. Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol. Cell Biol 24, 8467–8476 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kouzarides, T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 19, 1176–1179 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Glaser, K.B. et al. Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol. Cancer Ther. 2, 151–163 (2003).

    CAS  PubMed  Google Scholar 

  22. Langley, B., Brochier, C. & Rivieccio, M.A. Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. Stroke 40, 2899–2905 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Kubo, M. et al. A nonsynonymous SNP in PRKCH (protein kinase C η) increases the risk of cerebral infarction. Nat. Genet. 39, 212–217 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Conrad, D.F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Teo, Y.Y. et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23, 2741–2746 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

  27. The UK Parkinson's Disease Consortium & The Wellcome Trust Case Control Consortium 2. Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Hum. Mol. Genet. 20, 345–353 (2011).

  28. Bellenguez, C. et al. A robust clustering algorithm for identifying problematic samples in genome-wide association studies. Bioinformatics 28, 134–135 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Browning, B.L. & Browning, S. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210–223 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Su, Z., Cardin, N., Donnelly, P. & Marchini, J. A Bayesian method for detecting and characterizing allelic heterogeneity and boosting signals in genome-wide association studies. Stat. Sci. 24, 430–450 (2009).

    Article  Google Scholar 

Download references


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.

Author information

Authors and Affiliations




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.

Corresponding authors

Correspondence to Peter Donnelly or Hugh S Markus.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

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

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing