© 2007 The Royal College of Psychiatrists
SPECIAL ARTICLES |
Schizophrenia: a common disease caused by multiple rare alleles
Department of Psychiatry, University of Washington, Seattle
Department of Epidemiology, Mailman School of Public Health, Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York
Department of Genome Sciences and Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, USA
Correspondence: Dr Jon McClellan, Department of Psychiatry, Box 356560, University of Washington, Seattle, WA 98195, USA. Email: drjack{at}u.washington.edu
Funding detailed in Acknowledgements.
See invited commentary, pp.
200–203, this
issue
Schizophrenia is widely held to stem from the combined effects of multiple common polymorphisms, each with a small impact on disease risk. We suggest an alternative view: that schizophrenia is highly heterogeneous genetically and that many predisposing mutations are highly penetrant and individually rare, even specific to single cases or families. This `common disease – rare alleles' hypothesis is supported by recent findings in human genomics and by allelic and locus heterogeneity for other complex traits. We review the implications of this model for gene discovery research in schizophrenia.
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