1. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94304, USA
2. Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Illinois 60201, USA
3. Department of Computer Science, Columbia University, New York, New York 10027, USA
4. Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge CB2 2SR, UK
5. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff CF23 6BQ, UK
6. Department of Health Research and Policy, Stanford University, Stanford, California 94304, USA
7. Queensland Centre for Mental Health Research, and Queensland Institute for Medical Research, Brisbane, Queensland 4072, Australia
8. Department of Psychiatry, University of Colorado Denver, Aurora, Colorado 80045, USA
9. Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta, Georgia 30322, USA
10. Department of Psychiatry, Washington University, St Louis, Missouri 63110, USA
11. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA
12. School of Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA
13. Department of Psychiatry, University of California at San Francisco, San Francisco, California 94143, USA
14. Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
15. Department of Neurology, School of Medicine, University of California at San Francisco, San Francisco, California 94143, USA
16. Center for Genotyping and Analysis, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA
17. Departments of Psychiatry, and Human Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA

Correspondence to: Pablo V. Gejman² Correspondence and requests for materials should be addressed to P.V.G. (Email: pgejman@mac.com).

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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