Brief Communication | Published:

Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder

Nature Genetics volume 40, pages 10561058 (2008) | Download Citation

Abstract

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 × 10−9) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 × 10−8, rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

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Acknowledgements

Study supported by US National Institute of Mental Health (MH062137, MH067288, P.S.; MH063445, J.W.S.; MH63420, V.L.N.; N01MH80001, G.S.S., M.E.T. and M.S. Bauer), NARSAD (R.H.P., S.P., J.F., P.S.); Johnson & Johnson Pharmaceutical Research & Development, Sylvan C. Herman Foundation, Stanley Medical Research Institute, Dauten Family, Merck Genome Research Institute (E.M.S.); and National Health Medical Research Council (MRC), Australia (M.A.R.F.). Broad Institute Center for Genotyping and Analysis supported by U54 RR020278, National Center for Research Resources. UCL sample collection supported by MDF–The Bipolar Organization, Neuroscience Research Charitable Trust, central London NHS Blood Transfusion Service, Priory Hospitals and UK MRC (G9623693N, G0500791). Dublin sample collection supported by the Health Research Board and Science Foundation Ireland; controls supplied by J. McPartlin, Trinity College Biobank. Edinburgh cohort collection supported by the Wellcome Trust, London, Chief Scientist Office of the Scottish Executive and MRC, London. WTCCC genotype analyses were funded by the Wellcome Trust and undertaken within the context of the WTCCC. WTCCC members are listed in Supplementary Note.

Author information

Author notes

    • Shaun M Purcell
    • , Pamela Sklar
    •  & Nick Craddock

    These authors contributed equally to this work.

Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Manuel A R Ferreira
    • , Yan A Meng
    • , Douglas M Ruderfer
    • , Jinbo Fan
    • , Roy H Perlis
    • , Jordan W Smoller
    • , Jennifer Stone
    • , Gary S Sachs
    • , Shaun M Purcell
    •  & Pamela Sklar
  2. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Manuel A R Ferreira
    • , Yan A Meng
    • , Roy H Perlis
    • , Jordan W Smoller
    • , Jennifer Stone
    • , Gary S Sachs
    • , Shaun M Purcell
    •  & Pamela Sklar
  3. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Manuel A R Ferreira
    • , Yan A Meng
    • , Douglas M Ruderfer
    • , Jinbo Fan
    • , Roy H Perlis
    • , Jordan W Smoller
    • , Jennifer Stone
    • , Shaun M Purcell
    •  & Pamela Sklar
  4. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Manuel A R Ferreira
    • , Yan A Meng
    • , Douglas M Ruderfer
    • , Jinbo Fan
    • , Roy H Perlis
    • , Jordan W Smoller
    • , Jennifer Stone
    • , Kimberly Chambert
    • , Edward M Scolnick
    • , Shaun M Purcell
    •  & Pamela Sklar
  5. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Manuel A R Ferreira
    • , Yan A Meng
    • , Douglas M Ruderfer
    • , Jinbo Fan
    • , Roy H Perlis
    • , Jordan W Smoller
    • , Jennifer Stone
    • , Kimberly Chambert
    • , Jennifer Franklin
    • , Kristin G Ardlie
    • , Stacey B Gabriel
    • , Brendan Blumenstiel
    • , Matthew Defelice
    • , Edward M Scolnick
    • , Mark J Daly
    • , Shaun M Purcell
    •  & Pamela Sklar
  6. Genetic Epidemiology, Queensland Institute of Medical Research, QLD 4029, Australia.

    • Manuel A R Ferreira
  7. Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.

    • Michael C O'Donovan
    • , Ian R Jones
    • , George Kirov
    • , Elaine K Green
    • , Detelina Grozeva
    • , Ivan Nikolov
    • , Marian L Hamshere
    • , Valentina Moskvina
    • , Katherine Gordon-Smith
    • , Christine Fraser
    • , Peter A Holmans
    • , Michael J Owen
    •  & Nick Craddock
  8. Department of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham B15 2QZ, UK.

    • Lisa Jones
    • , Sian Caesar
    •  & Katherine Gordon-Smith
  9. Biostatistics and Bioinformatics Unit, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.

    • Ivan Nikolov
    • , Marian L Hamshere
    • , Valentina Moskvina
    •  & Peter A Holmans
  10. University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania 15213, USA.

    • Vishwajit L Nimgaonkar
  11. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Michael E Thase
  12. University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.

    • Michael E Thase
  13. University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.

    • Gerome Breen
    •  & David St Clair
  14. SGDP, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.

    • Gerome Breen
    • , Amanda Elkin
    • , Richard Williamson
    • , David A Collier
    • , Anne Farmer
    •  & Peter McGuffin
  15. Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin 8, Republic of Ireland.

    • Michael Gill
    • , Derek W Morris
    •  & Aiden P Corvin
  16. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.

    • Walter J Muir
    • , Kevin A McGhee
    • , Donald J MacIntyre
    • , Alan W MacLean
    • , Margaret Van Beck
    •  & Douglas H Blackwood
  17. Molecular Psychiatry Laboratory, Department of Mental Health Sciences, Windeyer Institute of Medical Sciences, University College London, 46 Cleveland Street, London W1T 4JF, UK.

    • Michelle Robinson
    • , Ana C P Pereira
    • , Radhika Kandaswamy
    • , Andrew McQuillin
    • , Nicholas J Bass
    • , Jacob Lawrence
    • , Adebayo Anjorin
    • , David Curtis
    •  & Hugh M Gurling
  18. School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

    • Allan H Young
    •  & I Nicol Ferrier
  19. UBC Institute of Mental Health, 2255 Wesbrook Mall, Detwiller Pavilion Vancouver, British Columbia, Canada V6T 2A1.

    • Allan H Young
  20. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Edward M Scolnick
    •  & Pamela Sklar
  21. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Mark J Daly
  22. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Mark J Daly
  23. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Mark J Daly

Consortia

  1. Wellcome Trust Case Control Consortium

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

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Contributions

Writing group: M.A.R.F., P.S., N.C., S.M.P. Analytic group: S.M.P., M.A.R.F., Y.A.M., D.M.R., J. Fan, M.J.D., P.A.H., M.C.O. N.C., P.S. Project management: P.S., E.M.S., A.P.C., D.H.B., H.M.G., M.C.O., N.C. Clinical characterization for STEP-BD: J.W.S., V.L.N., R.H.P., M.E.T., G.S.S. Clinical characterization for Trinity College Dublin: D.W.M., M.G., A.P.C. Clinical characterization for University of Edinburgh: W.J.M., K.A.M., D.J.M., A.W.M., M.V.B., D.H.B. Clinical characterization for University College London: A. McQuillin, N.J.B., M.R., J.L., A.C.P.P., R.K, A.A., D.C., H.M.G. Clinical characterization, phenotype assessment and sample management and curation for WTCCC: G.B., D.S. (Aberdeen); S.C., K.G.-S. L.J. (Birmingham); C.F., E.K.G., D.G., M.L.H., P.A.H., I.R.J., G.K., V.M., I.N., M.C.O., M.J.O., N.C. (Cardiff); D.A.C., A.E., A.F., R.W., P.M. (London); A.H.Y., I.N.F. (Newcastle). DNA sample QC and genotyping for ED-DUB-STEP2: K.C., J.S., J. Fan, J. Franklin, K.G.A., S.B.G., B.B., M.D.

Corresponding authors

Correspondence to Pamela Sklar or Nick Craddock.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Methods, Supplementary Figures 1–5, Supplementary Tables 1–10, Supplementary Note

About this article

Publication history

Received

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Published

DOI

https://doi.org/10.1038/ng.209

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