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Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Nature volume 460, pages 748752 (06 August 2009) | Download Citation


This article has been updated


Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%1,2. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

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Change history

  • 06 August 2009

    The subheading for Table 1b was changed on 6 August 2009.


  1. 1.

    & Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am. J. Med. Genet. 97, 12–17 (2000)

  2. 2.

    , & Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003)

  3. 3.

    et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genet. 40, 1053–1055 (2008)

  4. 4.

    & The NOTCH4 locus is associated with susceptibility to schizophrenia. Nature Genet. 25, 376–377 (2000)

  5. 5.

    et al. Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project. Immunogenetics 60, 1–18 (2008)

  6. 6.

    et al. Common variants conferring risk of schizophrenia. Nature 10.1038/nature08186 (this issue)

  7. 7.

    et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 10.1038/nature08192 (this issue)

  8. 8.

    The correlation between relatives on the supposition of Mendelian inheritance. Philos. Trans. R. Soc. Edinb. 52, 399–433 (1918)

  9. 9.

    & A polygenic theory of schizophrenia. Proc. Natl Acad. Sci. USA 58, 199–205 (1967)

  10. 10.

    , & Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 17, 1520–1528 (2007)

  11. 11.

    , & Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr. Bull. 32, 9–16 (2006)

  12. 12.

    et al. Whole-genome association study of bipolar disorder. Mol. Psychiatry 13, 558–569 (2008)

  13. 13.

    The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007)

  14. 14.

    , , & Fertility of first-degree relatives of patients with schizophrenia: a three generation perspective. Schizophr. Res. 91, 238–245 (2007)

  15. 15.

    , & Schizophrenia: a common disease caused by multiple rare alleles. Br. J. Psychiatry 190, 194–199 (2007)

  16. 16.

    , & Phenotypic and genetic complexity of psychosis. Invited commentary on. Schizophrenia: a common disease caused by multiple rare alleles. Br. J. Psychiatry 190, 200–203 (2007)

  17. 17.

    International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008)

  18. 18.

    et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008)

  19. 19.

    et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genet. 40, 880–885 (2008)

  20. 20.

    et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nature Genet. 40, 575–583 (2008)

  21. 21.

    et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234–239 (2009)

  22. 22.

    Psychiatric GWAS Consortium Steering Committee. A framework for interpreting genome-wide association studies of psychiatric disorders. Mol. Psychiatry 14, 10–17 (2009)

  23. 23.

    Psychiatric GWAS Consortium Coordinating Committee. Genomewide association studies: history, rationale and prospects for psychiatric disorders. Am. J. Psychiatry 166, 540–556 (2009)

  24. 24.

    Dissecting the phenotype in genome-wide association studies of psychiatric illness. Br. J. Psychiatry 10.1192/bjp.bp.108.063156 (in the press)

  25. 25.

    , & HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590–1605 (2008)

  26. 26.

    The case of the missing heritability. Nature 456, 18–21 (2008)

  27. 27.

    et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nature Genet. 40, 1253–1260 (2008)

  28. 28.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007)

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We thank the patients and families who contributed to these studies. We also thank E. Lander, N. Patterson and members of the Medical and Population Genetics group at the Broad Institute of Harvard and Massachusetts Institute of Technology for valuable discussion, and members of the Broad Biological Samples and Genetic Analysis Platforms for sample management and genotyping. We particularly thank D. Levinson and P. Gejman for allowing access to the MGS samples, and J. Shi for analytic support with the MGS samples. The group at the Stanley Center for Psychiatric Research at the Broad Institute was supported by the Stanley Medical Research Institute (E.M.S.), the Sylvan C. Herman Foundation (E.M.S.), and MH071681 (P.S.). The Cardiff University group was supported by a Medical Research Council (UK) Programme grant and the National Institutes of Mental Health (USA) (CONTE: 2 P50 MH066392-05A1). The group at the Karolinska Institutet was supported by the Swedish Council for Working Life and Social Research (FO 184/2000; 2001-2368). The Massachusetts General Hospital group was supported by the Stanley Medical Research Institute (P.S.), MH071681 and MH077139 (P.S.) and a Narsad Young Investigator Award (S.M.P.). The group at the Queensland Institute of Medical Research was supported by the Australian National Health and Medical Research Council (grants 389892, 442915, 496688 and 496674) and thanks S. Gordon for data preparation. The Trinity College Dublin group was supported by Science Foundation Ireland, the Health Research Board (Ireland), the Stanley Medical Research Institute and the Wellcome Trust; Irish controls were supplied by J. McPartlin from the Trinity College Biobank. The work at the University of Aberdeen was partly funded by GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. University College London clinical and control samples were collected with support from the Neuroscience Research Charitable Trust, the Camden and Islington Mental Health and Social Care Trust, East London and City Mental Heath Trust, the West Berkshire NHS Trust, the West London Mental Health Trust, Oxfordshire and Buckinghamshire Mental Health Partnership NHS Trust, South Essex Partnership NHS Foundation Trust, Gloucestershire Partnership NHS Foundation Trust, Mersey Care NHS Trust, Hampshire Partnership NHS Trust and the North East London Mental Health Trust. The collection of the University of Edinburgh cohort was supported by the Wellcome Trust Clinical Research Facility (Edinburgh) and grants from The Wellcome Trust, London and the Chief Scientist Office of the Scottish Government. The group at the University of North Carolina, Chapel Hill, was supported by MH074027, MH077139 and MH080403, the Sylvan C. Herman Foundation (P.F.S.) and the Stanley Medical Research Institute (P.F.S.). The group at the University of Southern California thanks the patients and their families for their collaboration, and acknowledges the support of the National Institutes of Mental Health and the Department of Veterans Affairs.

Author information


  1. Psychiatric and Neurodevelopmental Genetics Unit,

    • Shaun M. Purcell
    • , Jennifer L. Stone
    • , Pamela Sklar
    • , Shaun M. Purcell (Leader)
    • , Douglas M. Ruderfer
    • , Pamela Sklar (Leader)
    •  & Manuel A. R. Ferreira
  2. Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

    • Shaun M. Purcell
    • , Jennifer L. Stone
    • , Pamela Sklar
    • , Shaun M. Purcell (Leader)
    • , Douglas M. Ruderfer
    • , Edward M. Scolnick
    • , Pamela Sklar (Leader)
    • , Andrew N. Kirby
    • , Manuel A. R. Ferreira
    •  & Mark J. Daly
  3. Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Jennifer L. Stone
    • , Pamela Sklar
    • , Shaun M. Purcell (Leader)
    • , Douglas M. Ruderfer
    • , Shaun M. Purcell
    • , Edward M. Scolnick
    • , Pamela Sklar (Leader)
    • , Andrew N. Kirby
    • , Manuel A. R. Ferreira
    • , Mark J. Daly
    •  & Kimberly Chambert
  4. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Jennifer L. Stone
    • , Pamela Sklar
    • , Shaun M. Purcell (Leader)
    • , Douglas M. Ruderfer
    • , Shaun M. Purcell
    • , Pamela Sklar (Leader)
    • , Andrew N. Kirby
    • , Manuel A. R. Ferreira
    • , Mark J. Daly
    • , Kimberly Chambert
    • , Finny Kuruvilla
    • , Stacey B. Gabriel
    • , Kristin Ardlie
    • , Jennifer L. Moran
    •  & Edward M. Scolnick
  5. Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia.

    • Naomi R. Wray
    • , Peter M. Visscher
    •  & Stuart Macgregor
  6. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff C14 4XN, UK.

    • Michael C. O'Donovan
    • , Peter A. Holmans
    • , Michael C. O’Donovan
    • , Nick J. Craddock
    • , George K. Kirov
    • , Michael J. Owen
    • , Nigel M. Williams
    • , Lyudmila Georgieva
    • , Ivan Nikolov
    • , N. Norton
    •  & H. Williams
  7. Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

    • Patrick F. Sullivan
    •  & Patrick Sullivan
  8. Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JF, UK.

    • Andrew McQuillin
    • , Hugh Gurling
    • , Khalid Choudhury
    • , Susmita Datta
    • , Jonathan Pimm
    • , Vinay Puri
    • , Robert Krasucki
    • , Jacob Lawrence
    •  & Nicholas Bass
  9. Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.

    • Derek W. Morris
    • , Colm T. O’Dushlaine
    • , Aiden Corvin
    • , Michael Gill
    • , Colm T. O'Dushlaine
    • , Elaine Kenny
    •  & Emma M. Quinn
  10. Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.

    • Douglas H. R. Blackwood
    • , Walter J. Muir
    • , Kevin A. McGhee
    • , Ben Pickard
    • , Pat Malloy
    • , Alan W. Maclean
    •  & Margaret Van Beck
  11. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

    • Christina M. Hultman
    • , Paul Lichtenstein
    •  & Emma F. Thelander
  12. Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, SE-750 17 Uppsala, Sweden.

    • Christina M. Hultman
  13. Center for Genomic Psychiatry, University of Southern California, Los Angeles, California 90033, USA.

    • Carlos N. Pato
    • , Michele T. Pato
    • , Helena Medeiros
    • , Celia Carvalho
    • , Ayman Fanous
    • , David Conti
    •  & James A. Knowles
  14. Institute of Medical Sciences,

    • David St Clair
    •  & Soh Leh Kuan
  15. Department of Mental Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.

    • Caroline Crombie
    •  & Gillian Fraser
  16. Department of Medical Genetics, University Hospital Maichin Dom, Sofia 1431, Bulgaria.

    • Draga Toncheva
  17. Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia 1431, Bulgaria.

    • Vihra Milanova
  18. West Berkshire NHS Trust, 25 Erleigh Road, Reading RG3 5LR, UK.

    • Srinivasa Thirumalai
  19. Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK.

    • Digby Quested
  20. Ravenscraig Hospital, Inverkip Road, Greenock PA16 9HA, UK.

    • Nicholas Walker
  21. State University of New York – Upstate Medical University, Syracuse, New York 13210, USA.

    • Frank Middleton
    •  & Christopher Morley
  22. Washington VA Medical Center, Washington DC 20422, USA.

    • Ayman Fanous
  23. Department of Psychiatry, Georgetown University School of Medicine, Washington DC 20057, USA.

    • Ayman Fanous
  24. Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

    • Ayman Fanous
  25. Department of Psychiatry, Sao Miguel, 9500-310 Azores, Portugal.

    • Carlos Paz Ferreira
  26. Department of Psychiatry University of Coimbra, 3004-504 Coimbra, Portugal.

    • Antonio Macedo
    •  & M. Helena Azevedo


  1. The International Schizophrenia Consortium

    Manuscript preparation

    Data analysis

    GWAS analysis subgroup

    Polygene analyses subgroup

    Management committee

    Cardiff University

    Karolinska Institutet/University of North Carolina at Chapel Hill

    Trinity College Dublin

    University College London

    University of Aberdeen

    University of Edinburgh

    Queensland Institute of Medical Research

    University of Southern California

    Massachusetts General Hospital

    Stanley Center for Psychiatric Research and Broad Institute of MIT and Harvard


    Corresponding authors

    Correspondence to Shaun M. Purcell or Pamela Sklar or Pamela Sklar or Pamela Sklar or Shaun M. Purcell or Pamela Sklar (Leader) or Shaun M. Purcell or Pamela Sklar or Shaun M. Purcell or Pamela Sklar.

    Supplementary information

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    1. 1.

      Supplementary Information

      This file contains Supplementary Notes and Data with Supplementary Tables 1-18, Supplementary Figures 1-8 with Legends and Supplementary References.

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