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

Abstract

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 ¼ 0.0070), and MDD (P ¼ 0.011) with increased risk associated with the deletion variant (GPR50 D502-505 ). When the analysis was restricted to female subjects, the associations with BPAD and MDD increased in significance (P ¼ 0.00023 and P ¼ 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 ¼ 0.0096); and female SCZ and an intronic SNP (P ¼ 0.0014). No association was detected in males with either MDD, BPAD or SCZ. These results suggest that GPR50 D502-505 , 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. Bipolar affective disorder (BPAD) is a severe psychiatric disorder affecting approximately 1% of the world's population, and shows no difference in lifetime prevalence between male and female subjects. Twin and adoption studies have demonstrated a strong genetic component, with a concordance in BPAD between monozygotic twins of 60%. 1 Major depressive disorder (MDD) has a lifetime prevalence of 17% with women twice as likely as men to develop the disorder. 2 Estimates of the heritability of MDD vary, but a meta-analysis of studies gives a point estimate of heritability of liability to MDD of 0.37. 3 Schizophrenia (SCZ), as with BPAD, has an estimated frequency of 1% in the population, but heritability estimates suggest that it has a larger genetic component than either BPAD or MDD, with monozygotic twins giving a point estimate of comorbidity of 0.81 in another recent meta-analysis. 4 Despite the strong genetic component in these major psychiatric disorders, there are also strong environmental influences.Linkage to Xq28 has been studied many times in BPAD. Two loci, colour-blindness (CB), and glucose-6-phosphate dehydrogenase (G6PD), have been detected through linkage and association in more than one population. 5 Most significant are LOD scores of 8.1 and 7.35 between CB and BPAD in the American and Belgian populations, respectively, although reanalysis of much of the data from positive linkage results on the X chromosome has resulted in much reduced evidence for linkage and suggestions of ascertainment bias. 6-9 Several more recent studies have again renewed interest in the distal end of Xq, although the region implicated in these studies (Xq24-28) is larger than that depicted in the earlier reports. 5,[...

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

“…57 Sex-specific associations with schizophrenia have been reported for the catechol-O-methyltransferase gene 58 and several other genes. 59,60 It was also argued recently that sex may play a more important role in brain structure and psychiatric disorders than commonly acknowledged. [61][62][63] Our finding is consistent with this converging evidence.…”

Interleukin 3 and schizophrenia: the impact of sex and family history

“…53 Sex-specific associations with schizophrenia have been reported for the catechol omethyltransferase gene 38 and several other genes. 54,55 It was also argued recently that sex may play a more important role in brain structure and psychiatric disorders than commonly acknowledged. [56][57][58] Our finding is consistent with this converging evidence.…”

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

“…A female-specific association between BPAD and/or SCZ has been previously observed in both GPR50 15 and CREB1. 36 However, we cannot definitively say that there is no effect in males because the 95% CIs of the ORs in the male groups overlap with those of the ORs in the female samples where the significance was observed, indicating that there is no significant difference between their respective ORs.…”

“…Thus, we deemed it necessary to test the hypotheses that GPR78 may be involved in the pathogenesis of BPAD, SCZ or both BPAD and SCZ, in which all affected individuals were grouped together, as it has been previously suggested that the two psychiatric illnesses may share susceptibility loci. 33,34 Similarly, owing to evidence of differences between males and females in the manifestation of psychiatric illness 35 and from findings of sex-specific association in the analysis of other candidate genes, 15,36 analysis was also carried out on samples separated on the basis of gender.…”

“…Several members of this family have already been implicated in the pathophysiology of psychiatric illness. [13][14][15] GPR78 was identified by virtue of its homology to orphan GPR26, which was identified in human and rat. 16,17 Rat GPR26 encodes a 317-amino-acid protein distantly related to the serotonin 5-HT5a and gastrinreleasing hormone BB2 receptors.…”