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

Céline Bellenguez, Steve Bevan, Andreas Gschwendtner, Chris C.A. Spencer, Annette I. Burgess, Matti Pirinen, Caroline A. Jackson, Matthew Traylor, Amy Strange, Zhan Su, Gavin Band, Paul D. Syme, Rainer Malik, Joanna Pera, Norrving Bo, Robin Lemmens, Colin Freeman, Renata Schanz, Tom James, Deborah PooleLee Murphy, Helen Segal, Lynelle Cortellini, Yu Ching Cheng, Daniel Woo, Michael A. Nalls, Bertram Müller-Myhsok, Christa Meisinger, Udo Seedorf, Helen Ross-Adams, Steven Boonen, Dorota Wloch-Kopec, Valerie Valant, Julia Slark, Karen Furie, Hossein Delavaran, Cordelia Langford, Panos Deloukas, Sarah Edkins, Sarah Hunt, Emma Gray, Serge Dronov, Leena Peltonen, Solveig Gretarsdottir, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, Giorgio B. Boncoraglio, Eugenio A. Parati, John Attia, Elizabeth Holliday, Chris Levi, Maria Grazia Franzosi, Anuj Goel, Anna Helgadottir, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Audrey Duncanson, Janusz Jankowski, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Bradford B. Worrall, Steven J. Kittner, Braxton D. Mitchell, Brett Kissela, James F. Meschia, Vincent Thijs, Arne Lindgren, Mary Joan MacLeod, Agnieszka Slowik, Matthew Walters, Jonathan Rosand, Pankaj Sharma, Martin Farrall, Cathie L.M. Sudlow, Peter M. Rothwell, Martin Dichgans, Peter Donnelly*, Hugh S. Markus

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

333 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)328-333
Number of pages6
JournalNature Genetics
Issue number3
Publication statusPublished - Mar 2012

Bibliographical note

Funding Information:
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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