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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: 15.15). 06/2005; 10(5):470-8. DOI: 10.1038/sj.mp.4001593
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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=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).
    Brain and Behavior 02/2015; 5(3). DOI:10.1002/brb3.313
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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.
    British Journal of Pharmacology 09/2014; 172(13). DOI:10.1111/bph.12942 · 4.99 Impact Factor
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    • "er psychiatric diseases . For example , for schizophrenia , the protective effect of PDE4B in females [ Pickard et al . , 2007 ] and at risk effect of TNFa gene in males [ Sacchetti et al . , 2007 ] have been recently reported , whereas , for major depression and bipolar disorder , a female - specific risk effect has been observed for GPR50 gene [ Thomson et al . , 2005 ] ."
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    ABSTRACT: Impairment of glutamatergic neurotransmission is one of the major hypotheses proposed to explain the neurobiology of schizophrenia. Therefore, the genes involved in the glutamate neurotransmitter system could be considered potential candidate genes for schizophrenia susceptibility. A systematic study on alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor genes has been carried out and the results obtained from the analysis on GRIA2, GRIA3 and GRIA4 are reported. No evidence of association with schizophrenia was found for the GRIA2 and GRIA4 genes; strong evidence of association with schizophrenia was found for GRIA3. This X-linked gene showed a different behavior in the two genders; a positive association with schizophrenia was observed among females but not in males. Female carriers of rs1034428 A allele were found to have a 2.19-fold higher risk of developing schizophrenia compared to non-carriers and 3.28-fold higher risk for developing a non-paranoid phenotype. The analysis at the haplotype level showed that susceptibility to schizophrenia was associated with the specific haplotype rs989638-rs1034428-rs2227098 CAC (P = 0.0008). We conclude that, of the three AMPA genes analyzed here, only GRIA3 seems to be involved in the pathogenesis of schizophrenia, but only in females.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2008; 147B(6):745-53. DOI:10.1002/ajmg.b.30674 · 3.27 Impact Factor
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