Letter | Published:

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

Nature Genetics volume 44, pages 328333 (2012) | Download Citation

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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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.

Author information

Author notes

    • Céline Bellenguez
    •  & Steve Bevan

    These authors contributed equally to this work.

    • Peter Donnelly
    •  & Hugh S Markus

    These authors jointly directed this work.

    • Leena Peltonen

    Deceased.

Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Céline Bellenguez
    • , Chris C A Spencer
    • , Matti Pirinen
    • , Amy Strange
    • , Zhan Su
    • , Gavin Band
    • , Colin Freeman
    • , Anuj Goel
    • , Anna Helgadottir
    • , Anna Rautanen
    • , Martin Farrall
    •  & Peter Donnelly
  2. Stroke and Dementia Research Group, St. George's University of London, London, UK.

    • Steve Bevan
    • , Matthew Traylor
    • , Tom James
    •  & Hugh S Markus
  3. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany.

    • Andreas Gschwendtner
    • , Rainer Malik
    •  & Martin Dichgans
  4. Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK.

    • Annette I Burgess
    • , Deborah Poole
    • , Helen Segal
    •  & Peter M Rothwell
  5. Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK.

    • Caroline A Jackson
    •  & Cathie L M Sudlow
  6. Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.

    • Paul D Syme
    •  & Mary Joan Macleod
  7. Department of Neurology, Jagiellonian University Medical College, Krakow, Poland.

    • Joanna Pera
    • , Helen Ross-Adams
    • , Dorota Wloch-Kopec
    •  & Agnieszka Slowik
  8. Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden.

    • Bo Norrving
    • , Hossein Delavaran
    •  & Arne Lindgren
  9. Department of Neurology, Skåne University Hospital, Lund, Sweden.

    • Bo Norrving
    • , Hossein Delavaran
    •  & Arne Lindgren
  10. Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

    • Robin Lemmens
    •  & Vincent Thijs
  11. Vesalius Research Center, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.

    • Robin Lemmens
    •  & Vincent Thijs
  12. Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK.

    • Renata Schanz
    • , Julia Slark
    •  & Pankaj Sharma
  13. Wellcome Trust Clinical Research Facility Genetics Core Laboratory, University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • Lee Murphy
  14. Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Lynelle Cortellini
    • , Valerie Valant
    • , Karen Furie
    •  & Jonathan Rosand
  15. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Lynelle Cortellini
    • , Valerie Valant
    •  & Jonathan Rosand
  16. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Yu-Ching Cheng
    •  & Braxton D Mitchell
  17. Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Yu-Ching Cheng
    •  & Braxton D Mitchell
  18. Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

    • Daniel Woo
    •  & Brett Kissela
  19. Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.

    • Michael A Nalls
  20. Max Planck Institute of Psychiatry, Munich, Germany.

    • Bertram Müller-Myhsok
  21. Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology II, Neuherberg, Germany.

    • Christa Meisinger
  22. Leibniz–Institut für Arterioskleroseforschung, Universität Münster, Münster, Germany.

    • Udo Seedorf
  23. Division of Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium.

    • Steven Boonen
  24. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Cordelia Langford
    • , Panos Deloukas
    • , Sarah Edkins
    • , Sarah Hunt
    • , Emma Gray
    • , Serge Dronov
    •  & Leena Peltonen
  25. deCODE Genetics, Reykjavik, Iceland.

    • Solveig Gretarsdottir
    • , Gudmar Thorleifsson
    • , Unnur Thorsteinsdottir
    • , Kari Stefansson
    •  & Anna Helgadottir
  26. University of Iceland, Faculty of Medicine, Reykjavik, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson
  27. Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milan, Italy.

    • Giorgio B Boncoraglio
    •  & Eugenio A Parati
  28. Centre for Brain and Mental Health Research, University of Newcastle, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

    • John Attia
    • , Elizabeth Holliday
    •  & Chris Levi
  29. Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

    • Maria-Grazia Franzosi
  30. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.

    • Anuj Goel
    • , Anna Helgadottir
    •  & Martin Farrall
  31. Centre for Child Health Research, University of Western Australia, West Perth, Western Australia, Australia.

    • Jenefer M Blackwell
  32. Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK.

    • Jenefer M Blackwell
  33. Division of Psychological Medicine and Psychiatry, Biomedical Research Centre for Mental Health, Institute of Psychiatry, King's College London, London, UK.

    • Elvira Bramon
  34. The University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.

    • Matthew A Brown
  35. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Juan P Casas
  36. Department of Epidemiology and Public Health, University College London, London, UK.

    • Juan P Casas
  37. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.

    • Aiden Corvin
  38. Molecular and Physiological Sciences, The Wellcome Trust, London, London, UK.

    • Audrey Duncanson
  39. Centre for Gastroenterology, Barts and the London School of Medicine and Dentistry, London, UK.

    • Janusz Jankowski
  40. Division of Clinical Pharmacology, University of Oxford, Oxford, UK.

    • Janusz Jankowski
  41. Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.

    • Christopher G Mathew
    •  & Richard C Trembath
  42. Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
  43. Social, Genetic and Developmental Psychiatry Centre, King's College London Institute of Psychiatry, Denmark Hill, London, UK.

    • Robert Plomin
  44. University of Cambridge Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, UK.

    • Stephen J Sawcer
  45. National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and University College London Institute of Ophthalmology, London, UK.

    • Ananth C Viswanathan
  46. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, University College London, London, UK.

    • Nicholas W Wood
  47. Department of Neurology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

    • Bradford B Worrall
  48. Department of Public Health Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

    • Bradford B Worrall
  49. Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Steven J Kittner
  50. Baltimore Geriatric Research, Education, and Clinical Center, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, USA.

    • Steven J Kittner
  51. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.

    • James F Meschia
  52. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

    • Matthew Walters
  53. Department of Statistics, University of Oxford, Oxford, UK.

    • Peter Donnelly

Consortia

  1. The International Stroke Genetics Consortium (ISGC)

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

  2. the Wellcome Trust Case Control Consortium 2 (WTCCC2)

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

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Peter Donnelly or Hugh S Markus.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1–6, Supplementary Figure 1 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.1081

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