Letter

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

  • Nature Genetics volume 44, pages 11471151 (2012)
  • doi:10.1038/ng.2397
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Abstract

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10−8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10−4; discovery and replication combined OR = 1.21, P = 4.7 × 10−8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

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Acknowledgements

A complete list of funding acknowledgments is included in the Supplementary Note. We are grateful to the participants with ischemic stroke and also to their families for participating in this study. Australian population control data were derived from the Hunter Community Study. We also thank the University of Newcastle for funding and the men and women of the Hunter region who participated in this study. This research was funded by grants from the Australian National Health and Medical Research Council (NHMRC; project grant 569257), the Australian National Heart Foundation (NHF; project grant G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme and the Vincent Fairfax Family Foundation in Australia. E.G.H. is supported by the Australian NHMRC Fellowship scheme. J.G. is supported by a Practitioner Fellowship from the NHMRC and a Senior Clinical Research Fellowship from the Australian Office of Health and Medical Research. The principal funding for the Wellcome Trust Case Control Consortium 2 (WTCCC2) ischemic stroke study was provided by the Wellcome Trust, as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). This work was also supported by the European Community's Sixth Framework Programme (LSHM-CT-2007-037273), the Wellcome Trust core award (090532/Z/09/Z) and AstraZeneca. M. Farrall is a member of the Oxford British Heart Foundation (BHF) Centre of Research Excellence. The Siblings with Ischemic Stroke Study (SWISS) and the Ischemic Stroke Genetics Study (ISGS) were funded by grants from the US National Institute of Neurological Disorders and Stroke. Additional funding was provided by the US National Institute of Neurological Disorders and Stroke (U01NS069208). The Rotterdam Study received principal funding for this report from the Netherlands Heart Foundation (grant 2009B102).

Author information

Author notes

    • Rodney J Scott
    • , Christopher Levi
    •  & John Attia

    These authors jointly directed this work.

Affiliations

  1. Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

    • Elizabeth G Holliday
    • , Mark McEvoy
    • , Roseanne Peel
    •  & John Attia
  2. Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

    • Elizabeth G Holliday
    • , Tiffany-Jane Evans
    • , Pablo Moscato
    • , Rodney J Scott
    •  & John Attia
  3. School of Nursing and Midwifery, University of Newcastle, Newcastle, New South Wales, Australia.

    • Jane M Maguire
  4. Centre for Brain and Mental Health Research, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

    • Jane M Maguire
    • , Mark W Parsons
    • , Lisa F Lincz
    •  & Christopher Levi
  5. Department of Neurosciences, Gosford Hospital, Central Coast Area Health, Gosford, New South Wales, Australia.

    • Jane M Maguire
    •  & Jonathan W Sturm
  6. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.

    • Tiffany-Jane Evans
    • , Lisa F Lincz
    •  & Rodney J Scott
  7. Stroke Research Program, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.

    • Simon A Koblar
    • , Jim Jannes
    •  & Martin D Lewis
  8. Stroke Unit, Department of Neurology, Queen Elizabeth Hospital, Adelaide, South Australia, Australia.

    • Simon A Koblar
    •  & Jim Jannes
  9. School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

    • Jonathan W Sturm
    • , Mark McEvoy
    • , Roseanne Peel
    • , Christopher Oldmeadow
    •  & Wayne Smith
  10. Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia.

    • Graeme J Hankey
  11. School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.

    • Graeme J Hankey
  12. Department of Haematology, Royal Perth Hospital, Perth, Western Australia, Australia.

    • Ross Baker
  13. Centre for Thrombosis and Haemophilia, Murdoch University, Perth, Western Australia, Australia.

    • Ross Baker
  14. Vascular Biology Unit, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.

    • Jonathan Golledge
    •  & Erik Biros
  15. Department of Vascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia.

    • Jonathan Golledge
  16. Institute for Stroke and Dementia Research (ISD), Medical Center, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany.

    • Rainer Malik
    • , Andreas Gschwendtner
    •  & Martin Dichgans
  17. Public Health Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

    • Mark McEvoy
    • , Roseanne Peel
    •  & Wayne Smith
  18. Discipline of Genetics, School of Molecular & Biomedical Sciences, University of Adelaide, Adelaide, South Australia, Australia.

    • Martin D Lewis
  19. Hunter Haematology Research Group, Calvary Mater Newcastle Hospital, Newcastle, New South Wales, Australia.

    • Lisa F Lincz
  20. Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

    • Christopher Oldmeadow
  21. School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, New South Wales, Australia.

    • Pablo Moscato
  22. Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

    • Simona Barlera
  23. Stroke and Dementia Research Centre, St. George's University of London, London, UK.

    • Steve Bevan
    • , Matthew Traylor
    •  & Hugh S Markus
  24. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
    • , Bruce M Psaty
    •  & Kerri L Wiggins
  25. Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
    •  & Myriam Fornage
  26. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
    •  & Myriam Fornage
  27. Department of Cerebrovascular Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milan, Italy.

    • Giorgio B Boncoraglio
    •  & Eugenio A Parati
  28. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.

    • Thomas G Brott
    •  & James F Meschia
  29. Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.

    • Robert D Brown Jr
  30. Department of Medicine, University of Maryland, Baltimore, Maryland, USA.

    • Yu-Ching Cheng
    •  & Braxton D Mitchell
  31. Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, USA.

    • John W Cole
  32. School of Medicine, University of Maryland, Baltimore, Maryland, USA.

    • John W Cole
  33. Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK.

    • Ioana Cotlarciuc
    •  & Pankaj Sharma
  34. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • William J Devan
    •  & Jonathan Rosand
  35. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • William J Devan
    • , Karen L Furie
    •  & Jonathan Rosand
  36. Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.

    • William J Devan
    • , Karen L Furie
    •  & Jonathan Rosand
  37. deCODE Genetics, Reykjavik, Iceland.

    • Sólveig Grétarsdóttir
    • , Kari Stefansson
    • , Gudmar Thorleifsson
    •  & Unnur Thorsteinsdottir
  38. Department of Epidemiology, Erasmus Medical Center (MC)–University Medical Center, Rotterdam, The Netherlands.

    • M Arfan Ikram
    •  & Benjamin F J Verhaaren
  39. Department of Neurology, Erasmus MC–University Medical Center, Rotterdam, The Netherlands.

    • M Arfan Ikram
  40. Department of Radiology, Erasmus MC–University Medical Center, Rotterdam, The Netherlands.

    • M Arfan Ikram
    •  & Benjamin F J Verhaaren
  41. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • W T Longstreth Jr
    •  & Bruce M Psaty
  42. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • W T Longstreth Jr
  43. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • W T Longstreth Jr
  44. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Thomas H Mosley
  45. Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Michael A Nalls
  46. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  47. Group Health Research Institute, Group Health, Seattle, Washington, USA.

    • Bruce M Psaty
  48. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Kari Stefansson
    •  & Unnur Thorsteinsdottir
  49. Department of Neurology, University of Virginia, Charlottesville, Virginia, USA.

    • Bradford B Worrall
  50. Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK.

    • Cathie Sudlow
  51. Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Cathie Sudlow
  52. Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK.

    • Peter M Rothwell
  53. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Martin Farrall
  54. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.

    • Martin Farrall
  55. Division of Genetics, Hunter Area Pathology Service, Newcastle, New South Wales, Australia.

    • Rodney J Scott

Consortia

  1. The Australian Stroke Genetics Collaborative

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

  2. The International Stroke Genetics Consortium

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

  3. The Wellcome Trust Case Control Consortium 2

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

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Contributions

S.A.K., J.W.S., L.F.L., P.M., R.J.S., C.L. and J.A. designed the study. E.G.H. performed statistical analyses in the discovery cohort, meta-analyses of replication data and wrote the first draft of the manuscript. T.-J.E. and R.J.S. coordinated genotyping of the discovery cohort. J.M.M., J.G., J.J., G.J.H., R.B., M.W.P., J.W.S., L.F.L., C.L., M.M., R.P., W.S. and J.A. performed phenotype collection and data management in the Australian sample. E. Biros, M.D.L. and C.O. performed bioinformatic analyses. Replication data were provided by S. Barlera, S. Bevan, J.C.B., E. Boerwinkle, G.B.B., T.G.B., R.D.B., Y.-C.C., J.W.C., I.C., W.J.D., M. Fornage, K.L.F., S.G., A.G., M.A.I., W.T.L., R.M., J.F.M., B.D.M., T.H.M., M.A.N., E.A.P., B.M.P., P.S., K.S., G.T., M.T., U.T., B.F.J.V., K.L.W., B.B.W., C.S., P.M.R., M. Farrall, M.D., J.R. and H.S.M. All authors critically reviewed the manuscript and gave advice on the contents of the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Elizabeth G Holliday.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–12, Supplementary Figures 1–7 and Supplementary Note