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

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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.

Original languageEnglish (US)
Pages (from-to)328-333
Number of pages6
JournalNature Genetics
Volume44
Issue number3
DOIs
StatePublished - Mar 1 2012

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ASJC Scopus subject areas

  • Genetics

Cite this

Bellenguez, C., Bevan, S., Gschwendtner, A., Spencer, C. C. A., Burgess, A. I., Pirinen, M., Jackson, C. A., Traylor, M., Strange, A., Su, Z., Band, G., Syme, P. D., Malik, R., Pera, J., Bo, N., Lemmens, R., Freeman, C., Schanz, R., James, T., ... Markus, H. S. (2012). Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nature Genetics, 44(3), 328-333. https://doi.org/10.1038/ng.1081