Schizophrenia: a common disease caused by multiple rare alleles.

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.