Thomson PA, Wray NR, Thomson AM, Dunbar DR, Grassie MA, Condie A et al. Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor. Mol Psychiatry 10: 470-478

Medical Genetics Section, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, Scotland.
Molecular Psychiatry (Impact Factor: 14.5). 06/2005; 10(5):470-8. DOI: 10.1038/
Source: PubMed


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(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.

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    • "Rs561077 was not associated with depression prevalence, but was associated with a 12-year increased risk of incident depression (P = 0.009). These results thus support the earlier work by Thomson (Thomson et al. 2005), although the effect size is quite weak (1.8-fold increased risk). This could be explained by the " winners curse " , where a reduced effect size is commonly observed in replication studies (Ioannidis 2008). "
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    ABSTRACT: IntroductionDespite the explosion in genetic association studies over the last decade, clearly identified genetic risk factors for depression remain scarce and replication studies are becoming increasingly important. G-protein-coupled receptor 50 (GPR50) has been implicated in psychiatric disorders in a small number of studies, although not consistently.Methods Data were obtained from 1010 elderly men and women from the prospective population-based ESPRIT study. Logistic regression and survival models were used to determine whether three common GPR50 polymorphisms were associated with depression prevalence or the incidence of depression over 12-years. The analyses were adjusted for a range of covariates such as comorbidity and cholesterol levels, to determine independent associations.ResultsAll three variants showed some evidence of an association with late-life depression in women, although these were not consistent across outcomes, the overall effect sizes were relatively small, and most would not remain significant after correction for multiple testing. Women heterozygous for rs13440581, had a 1.6-fold increased risk of baseline depression, while the odds of depression comorbid with anxiety were increased fourfold for women homozygous for the minor allele of rs2072621. When depressed women at baseline were excluded from the analysis, however, neither variant was associated with the 12-year incidence of depression. In contrast, rs561077 was associated with a 1.8-fold increased risk of incident depression specifically. No significant associations were observed in men.DiscussionOur results thus provide only weak support for the involvement of GPR50 variants in late-life depression, which appear specific to certain subgroups of depressed individuals (i.e., women and those with more severe forms of depression).
    Full-text · Article · Feb 2015 · Brain and Behavior
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    • "Based on genotyping study in human subjects, Thomson et al. (2005) reported a link between polymorphisms in the GPR50 gene and major mental illness while other studies targeted the dopaminergic system in the striatum and found a possible role of GPR6, GPR52 and GPR88 in related neurodegenerative/psychiatric disorders. For instance, GPR6 was abundantly expressed in striatopallidal neurons and its depletion reduces cAMP concentrations in the striatum and alters the striatal dopaminergic system. "
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    ABSTRACT: Seven transmembrane-spanning proteins (7TM), also called G protein-coupled receptors (GPCRs), are among the most versatile and evolutionary successful protein families. Out of the 400 non-odorant members identified in the human genome, approximately 100 remain orphans that have not been matched with an endogenous ligand. Apart from the classical deorphanization strategies, several alternative strategies provided recent new insights into the function of these proteins, which hold promise for high therapeutic potential. These alternative strategies consist of the phenotypic characterization of organisms silenced or overexpressing orphan 7TM proteins, the search for constitutive receptor activity and formation of protein complexes including 7TM proteins as well as the development of synthetic, surrogate, ligands. Taken together, a variety of ligand-independent functions can be attributed to orphan 7TM proteins that range from constitutive activity to complex formation with other proteins and include “true” orphans for which no ligand exist and “conditional” orphans that behave like orphans in the absence of ligand and as non-orphans in the presence of ligand.
    Full-text · Article · Sep 2014 · British Journal of Pharmacology
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    • "Specifically, Gpr50 expression in the brain is highly responsive to energy status being decreased by both fasting and high fat diet feeding [5], and Gpr50−/− mice demonstrate elevated metabolic rate, reduced fat accumulation, and partial resistance to diet-induced obesity. In humans, polymorphisms in Gpr50 have been linked to elevated circulating triglycerides and cholesterol levels [6], as well as psychiatric affective disorders including bipolar disorder [7], [8]. "
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    ABSTRACT: GPR50 is an orphan G-protein coupled receptor most closely related to the melatonin receptors. The physiological function of GPR50 remains unclear, although our previous studies implicate the receptor in energy homeostasis. Here, we reveal a role for GPR50 as a signalling partner and modulator of the transcriptional co-activator TIP60. This interaction was identified in a yeast-two-hybrid screen, and confirmed by co-immunoprecipitation and co-localisation of TIP60 and GPR50 in HEK293 cells. Co-expression with TIP60 increased perinuclear localisation of full length GPR50, and resulted in nuclear translocation of the cytoplasmic tail of the receptor, suggesting a functional interaction of the two proteins. We further demonstrate that GPR50 can enhance TIP60-coactiavtion of glucocorticoid receptor (GR) signalling. In line with in vitro results, repression of pituitary Pomc expression, and induction of gluconeogenic genes in liver in response to the GR agonist, dexamethasone was attenuated in Gpr50(-/-) mice. These results identify a novel role for GPR50 in glucocorticoid receptor signalling through interaction with TIP60.
    Full-text · Article · Aug 2011 · PLoS ONE
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