Study Report

Reference	Thomson, P. A.,2005(b) PMID: 15452587
Citation	Thomson, P. A., N. R. Wray, et al. (2005). Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor. Mol Psychiatry 10(5): 470-478.
Disease Type	Bipolar Disorder & Schizophrenia & Major Depressive Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	subjects with BPAD (264), major depressive disorder (MDD) (226), or schizophrenia (SCZ) (263) and ethnically matched controls (562)
SNP/Region/Marker Size	3 polymorphisms
Predominant Ethnicity	Caucasian
Population	Scottish
Gender	Male/female:302/260 in controls,121/143 in patients with BPAD,90/136 in patients with MDD,187/76 in patients with SCZ,7/15 in patients with BPspec

Sample Diagnosis	DSM
Sample Status	Subjects in the group bipolar affective disorder(BPAD) included those with diagnoses Bipolar 1 and Bipolar 2, and all had a history of at least two episodes of major depression. Subjects included in the MDD group had a history of at least two episodes of major depression. The interview of subjects with MDD included additional questions to elicit symptoms consistent with 'bipolar spectrum disorder' as defined by Ghaemi et al.19 The criteria for 'bipolar spectrum disorder' include: brief episodes of hypomanic symptoms of any duration less than 4 days; a first or second degree relative with bipolar disorder;symptoms of hypomania induced by antidepressant medication. In the first stages of analysis, subjects with MDD and 'bipolar spectrum' features were included in the group of major depression. The nosological status of 'bipolar spectrum' remains uncertain, but there are strong arguments for including these subjects in the bipolar group.20 Analyses were therefore carried out with MDD excluding'spectrum', and bipolar disorder including 'spectrum'. Control subjects were drawn from the same population in South East and South Central Scotland, and recruited from donors for the Scottish National Blood Transfusion service or from hospital staff.
Technique	genotyping
Statistical Method	The X2 contingency table tests were used to test for allelic association with case-control status and for differences in allele frequencies between cases with maternal or paternal family history. Unconditional logistic regression as implemented in UNPHASED22 was used to test for association with two- and three-marker haplotypes(haplotype frequencies were estimated using the EM algorithm). UNPHASED was also used to calculate|D'| and r2 measures of linkage disequilibrium from trio (parents and offspring) genotypes.
Result Summary	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(Delta502-505)). 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(Delta502-505), 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.