Abstract

We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10−5 in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 × 10−4), and the overall pattern of replication was unlikely to occur by chance (P = 9 × 10−8). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 × 10−7) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 × 10−9).

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Acknowledgements

The UK research was supported by grants from the MRC and the Wellcome Trust. We are grateful to the Wellcome Trust Case Control Consortium for access to control genotypes (and to the individuals acknowledged in that respect in ref. 4) and their contribution to the genome-wide study, and to the Welsh e-Science Centre at Cardiff University for access to computing resources for some of this work. In Dublin, the research was supported by Science Foundation Ireland, the Health Research Board (Ireland) and the Wellcome Trust. We are grateful to J. Waddington for sample recruitment. Irish controls were supplied by J. McPartlin and the Trinity College Biobank. In Bonn and Mannheim, the work was supported by the National Genomic Network of the 'Bundesministerium für Bildung und Forschung' (BMBF) and the Alfried Krupp von Bohlen und Halbach-Stiftung. We also thank the Department of Psychiatry, LMU Munich for clinical characterization of the Munich subjects and the processing of the samples. Recruitment in Munich was partially supported by GlaxoSmithKline. The Ashkenazi samples are part of the Hebrew University Genetic Resource.

Author information

Affiliations

  1. Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.

    • Michael C O'Donovan
    • , Nicholas Craddock
    • , Nadine Norton
    • , Hywel Williams
    • , Timothy Peirce
    • , Valentina Moskvina
    • , Ivan Nikolov
    • , Marian Hamshere
    • , Liam Carroll
    • , Lyudmila Georgieva
    • , Sarah Dwyer
    • , Peter Holmans
    • , Stanley Zammit
    • , Nigel M Williams
    • , George Kirov
    •  & Michael J Owen
  2. Department of Statistics, University of Oxford, OX1 3TG, UK.

    • Jonathan L Marchini
    • , Chris C A Spencer
    •  & Bryan Howie
  3. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0XY, UK.

    • Hin-Tak Leung
  4. Division of Molecular and Clinical Neurobiology, Ludwig-Maximilians-University, Nuβbaumstr. 7, 80336 Munich, Germany.

    • Annette M Hartmann
    • , Ina Giegling
    •  & Dan Rujescu
  5. Department of Psychiatry, Ludwig-Maximilians-University, Nuβbaumstr. 7, 80336 Munich, Germany.

    • Hans-Jürgen Möller
  6. Neuropsychiatric Genetics Research Group, School of Medicine, Trinity College Dublin 8, Ireland.

    • Derek W Morris
    • , Emma M Quinn
    • , Michael Gill
    •  & Aiden Corvin
  7. Bio-X Center, Shanghai Jiao Tong University, Shanghai 200030, China.

    • YongYong Shi
    •  & Lin He
  8. Shanghai Institute of Mental Health, Shanghai 200030, China.

    • GuoYin Feng
  9. Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53105, Germany.

    • Per Hoffmann
    • , Catalina Vasilescu
    • , Sven Cichon
    •  & Markus M Nöthen
  10. Institute of Human Genetics, University of Bonn, Bonn 53105, Germany.

    • Peter Propping
    • , Sven Cichon
    •  & Markus M Nöthen
  11. Department of Psychiatry, University of Bonn, Bonn 53105, Germany.

    • Wolfgang Maier
  12. Central Institute for Mental Health, Division Genetic Epidemiology in Psychiatry, Mannheim 68159, Germany.

    • Marcella Rietschel
  13. Genetic Basis of Mood and Anxiety Disorders, US National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Johannes Schumacher
    •  & Thomas G Schulze
  14. Department of Psychiatry, Fujita Health University School of Medicine, Aichi 470-1192, Japan.

    • Nakao Iwata
    •  & Masashi Ikeda
  15. Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.

    • Nakao Iwata
    •  & Masashi Ikeda
  16. Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem 91904, Israel.

    • Ariel Darvasi
    •  & Sagiv Shifman
  17. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

    • Lin He
  18. Center for Psychiatric Genetics, Evanston Northwestern Healthcare (ENH), Evanston, Illinois 60201, USA.

    • Jubao Duan
    • , Alan R Sanders
    •  & Pablo V Gejman
  19. Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60201, USA.

    • Jubao Duan
    • , Alan R Sanders
    •  & Pablo V Gejman
  20. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California 94305, USA.

    • Douglas F Levinson
  21. School of Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.

    • Nancy G Buccola
  22. The Queensland Centre for Mental Health Research and The Queensland Institute for Medical Research, Wacol, Queensland 4076, Australia.

    • Bryan J Mowry
  23. Department of Psychiatry, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.

    • Robert Freedman
  24. Atlanta Veterans Affairs Medical Center and Department of Psychiatry and Behavioral Sciences, Emory University, Decatur, Georgia 30033, USA.

    • Farooq Amin
  25. Mental Health Clinical Research Center and Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.

    • Donald W Black
  26. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.

    • Jeremy M Silverman
  27. Department of Psychiatry, University of California San Francisco, San Francisco, California 94121, USA.

    • William F Byerley
  28. Departments of Psychiatry, Washington University, St. Louis, Missouri 63108, USA.

    • C Robert Cloninger
  29. Departments of Genetics, Washington University, St. Louis, Missouri 63108, USA.

    • C Robert Cloninger

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Contributions

M.C.O'D., M.J.O., and N.C. directed this study and the collection of the UK sample. M.C.O'D. and M.J.O. took primary responsibility for drafting the manuscript assisted by N.N. and H.W. Collaborative scientific direction, replication sample collections, diagnoses and construction of case-control material were led by A.C., M.G., and D.W.M. (Ireland), D.R. (Munich, Germany), W.M., M.R., M.M.N., S.C., J.S. and P.P. (Bonn, Germany), G.K. (Bulgaria), L.H. and G.F. (China); N.I. (Japan) and S.S. and A.D. (Israel). J.L.M., C.C.A.S. and H.-T.L. were responsible for procedures related to calling Affymetrix genotypes. Replication genotyping was performed and analyzed by N.N., H.W., T.P., L.C., L.G. and S.D. (Cardiff); C.V. and P.Hoffmann (Bonn); Y.S. (China); S.S. (Israel); and M.I. (Japan). I.N. developed the database for the GWA project in which the data were stored, the primary analyses were performed and the results visualized. V.M. and P.Holmans supervised the association statistics to which N.N. additionally contributed. M.H. and N.C. were responsible for most of the quality control procedures. Additional scientific coordination of clinical sample collection and diagnosis was performed by S.Z., E.M.Q., A.M.H., H.-J.M., I.G. and T.G.S. All authors discussed the results and approved the manuscript.

Corresponding authors

Correspondence to Michael C O'Donovan or Michael J Owen.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–3, Supplementary Tables 1–3, Supplementary Methods, Supplementary Note

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DOI

https://doi.org/10.1038/ng.201

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