Schizophrenia and bipolar disorder are two major psychiatric illnesses that may share specific genetic risk factors to a certain extent. Increasing evidence suggests that the two disorders might be more closely related than previously considered. In order to test this hypothesis, we investigated a functional polymorphism -197C/G in XBP1, which was reported to increase the risk of bipolar disorder, in a case-control study (374 cases vs. 371 controls) to evaluate its genetic role in the pathogenesis of schizophrenia. In the present study, this polymorphism was found to be associated with schizophrenia both at allele (P = 0.034; OR = 1.26, 95% CI 1.02-1.55) and genotype levels (GG vs. CG + CC, 47.59% vs. 38.81%; P = 0.016, df = 1; OR = 1.43, 95% CI 1.07-1.92). Our current data suggest that -197C/G in XBP1 is also a genetic risk factor for schizophrenia. In addition, it presents a sex-dependent genetic effect for the disorder. (C) 2004 Elsevier Inc. All rights reserved.