AbstractWe investigated the possible involvement of OTX2, a homeobox gene crucial for forebrain development, in the pathogenesis of schizophrenia and bipolar disorder. The disruption of this gene results in cortical malformations and causes serotonergic and dopaminergic cells in the midbrain to be expressed in aberrant locations. Resequencing of DNA from OTX2 exons and surrounding introns from 60 individuals (15 schizophrenia, 15 bipolar disorder, 15 depression, and 15 control) revealed two intronic polymorphisms, rs2277499 (C/T) and rs28757218 (G/T), but no other variations. The minor allele of rs2277499 (T) did not associate with clinical diagnosis. However, using a Taqman genotyping assay, we found the rs28757218 minor allele (T) in 30 out of 720 (4.2%) individuals with bipolar disorder but only in 6 out of 526 (1.1%) control individuals (odds ratio 3.5, 95% confidence interval 1.4–10.4, P = 0.003). On the other hand, the rs28757218 minor allele was only found in 6 out of 458 (1.3%) individuals with schizophrenia. All individuals with the rs28757218 polymorphism were heterozygous for the allele. Based on this positive case‐control association finding, we conclude that variations in OTX2 might confer risk for the development of bipolar disorder. © 2007 Wiley‐Liss, Inc.