Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor

GPR50 is an orphan G protein-coupled receptor (GPCR) located on Xq28, a region previously implicated in multiple genetic studies of bipolar affective disorder (BPAD). Allele frequencies of three polymorphisms in GPR50 were compared in case–control studies between subjects with BPAD (264), major depressive disorder (MDD) (226), or schizophrenia (SCZ) (263) and ethnically matched controls (562). Significant associations were found between an insertion/deletion polymorphism in exon 2 and both BPAD ( P =0.0070), and MDD ( P =0.011) with increased risk associated with the deletion variant ( GPR50 Δ502–505 ). When the analysis was restricted to female subjects, the associations with BPAD and MDD increased in significance ( P =0.00023 and P =0.0064, respectively). Two other single-nucleotide polymorphisms (SNPs) tested within this gene showed associations between: the female MDD group and an SNP in exon 2 ( P =0.0096); and female SCZ and an intronic SNP ( P =0.0014). No association was detected in males with either MDD, BPAD or SCZ. These results suggest that GPR50 Δ502–505 , or a variant in tight linkage disequilibrium with this polymorphism, is a sex-specific risk factor for susceptibility to bipolar disorder, and that other variants in the gene may be sex-specific risk factors in the development of schizophrenia.