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Abstract

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission1. Recent studies implicate rare, large, high-penetrance copy number variants in some cases2, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 × 10-9). This region includes a histone gene cluster and several immunity-related genes—possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

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Change history

  • 06 August 2009

    Author affiliation five was changed on 6 August 2009.

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Primary accessions

Data deposits

Data have been deposited at dbGaP (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) under accessions phs000021.v2.p1 and phs000167.v1.p1, and the NIMH Center for Collaborative Genetic Studies on Mental Disorders (http://www.nimhgenetics.org) under studies 6, 29 and 29C.

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Acknowledgements

We thank the study participants, and the research staff at the study sites. This study was supported by funding from the National Institute of Mental Health (USA) and the National Alliance for Research on Schizophrenia and Depression. Genotyping of part of the sample was supported by the Genetic Association Information Network (GAIN), and by The Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT with support from the National Center for Research Resources (USA). The GAIN quality control team (G. R. Abecasis and J. Paschall) made important contributions to the project. We thank S. Purcell for assistance with PLINK.

Author Contributions J.S., D.F.L. and P.V.G. wrote the first draft of the paper. P.V.G., D.F.L., A.R.S., B.J.M., A.O., F.A., C.R.C., J.M.S., N.G.B., W.F.B., D.W.B., R.R.C. and R.F. oversaw the recruitment and clinical assessment of MGS participants, and the clinical aspects of the project and analysis. A.R.S., D.F.L. and P.V.G. performed database curation. D.F.L., J.S., I.P., F.D., P.A.H., A.S.W. and P.V.G. designed the analytical strategy and analysed the data. D.B.M. oversaw the Affymetrix 6.0 genotyping, and J.D., Y.Z., A.R.S. and P.V.G. performed the preparative genotyping and experimental work. J.R.O. contributed to the interpretation of data in the MHC/HLA region, and K.S.K. contributed to the approach to clinical data. P.V.G. coordinated the overall study. All authors contributed to the current version of the paper.

Author information

Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94304, USA

    • Jianxin Shi
    •  & Douglas F. Levinson
  2. Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Illinois 60201, USA

    • Jubao Duan
    • , Alan R. Sanders
    • , Yonglan Zheng
    •  & Pablo V. Gejman
  3. Department of Computer Science, Columbia University, New York, New York 10027, USA

    • Itsik Pe’er
  4. Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge CB2 2SR, UK

    • Frank Dudbridge
  5. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff CF23 6BQ, UK

    • Peter A. Holmans
  6. Department of Health Research and Policy, Stanford University, Stanford, California 94304, USA

    • Alice S. Whittemore
  7. Queensland Centre for Mental Health Research, and Queensland Institute for Medical Research, Brisbane, Queensland 4072, Australia

    • Bryan J. Mowry
  8. Department of Psychiatry, University of Colorado Denver, Aurora, Colorado 80045, USA

    • Ann Olincy
    •  & Robert Freedman
  9. Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta, Georgia 30322, USA

    • Farooq Amin
  10. Department of Psychiatry, Washington University, St Louis, Missouri 63110, USA

    • C. Robert Cloninger
  11. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Jeremy M. Silverman
  12. School of Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA

    • Nancy G. Buccola
  13. Department of Psychiatry, University of California at San Francisco, San Francisco, California 94143, USA

    • William F. Byerley
  14. Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA

    • Donald W. Black
    •  & Raymond R. Crowe
  15. Department of Neurology, School of Medicine, University of California at San Francisco, San Francisco, California 94143, USA

    • Jorge R. Oksenberg
  16. Center for Genotyping and Analysis, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA

    • Daniel B. Mirel
  17. Departments of Psychiatry, and Human Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA

    • Kenneth S. Kendler

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Competing interests

F.A. has received funds from Pfizer, Organon, and the Foundation for the National Institutes of Health. D.W.B. has received research support from Shire and Forest, has been on the speakers’ bureau for Pfizer, and has received consulting honoraria from Forest and Jazz.

Corresponding author

Correspondence to Pablo V. Gejman.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Methods, Supplementary Tables S1-S19, Supplementary Figures S1-S11 and Supplementary References.

  2. 2.

    Supplementary Data

    This file contains intensity plots for SNPs in the MHC region.

Excel files

  1. 1.

    Supplementary Data

    This file contains data for the MGS GWAS and for the meta-analysis of MGS with ISC and SGENE data.

  2. 2.

    Supplementary Data

    This file contains MGS GWAS results for 75 genes that have previously been considered candidate genes for schizophrenia, or closely related genes.

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DOI

https://doi.org/10.1038/nature08192

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