Macintyre DJ, McGhee KA, Maclean AW, Afzal M, Briffa K, Henry B et al. Association of GPR50, an X-linked orphan G protein-coupled receptor, and affective disorder in an independent sample of the Scottish population. Neurosci Lett 475: 169-173
A recent report detected association between GPR50, an orphan G protein-coupled receptor, and bipolar disorder (BD) in the Scottish population . We sought to replicate this study in a second sample from the same population, consisting of 338 patients with BD, 359 patients with major depressive disorder (MDD) and 913 control individuals. In addition, the effect of GPR50 genotype on clinical phenotype and treatment response was assessed in a subset of 56 patients with early onset MDD (eoMDD). We identified an association with BD in women with an intronic SNP, rs1202874, that withstood correction for multiple testing (p=0.0035, permuted p=0.037, OR=1.9, 95%CI 1.2-3.0). However, we failed to find an association with the previously associated Delta502-505 polymorphism (p=0.2). Combined analysis of this and the original samples did detect association between the deletion and susceptibility to BD in females, but with a reduced effect size (p=0.0006, permuted p=0.0024, OR=1.41, 95%CI 1.16-1.71). In the highly phenotyped eoMDD subgroup, we found an association between the Delta502-505 deletion polymorphism and age of onset (p=0.049), number of episodes (p=0.044), hypomanic symptoms (p=0.019), and initial thinking time (p=0.027), in women; and in family history of depression in men (p=0.038), uncorrected for multiple testing. No association was seen between Delta502-505 genotype and treatment response at 3 months. To our knowledge this is the first association of rs1202874 with BD and is the second positive association at the GPR50 locus.
"The first case–control study of 226 patients with MDD and 562 ethnically matched controls found that two GPR50 polymorphisms (rs13440581 and D502–505) were strongly associated with an increased risk of MDD in women (Thomson et al. 2005). On the other hand, another case–control study of 359 MDD patients and 913 controls undertaken in a very similar population (Macintyre et al. 2010), failed to find a significant association with four GRP50 polymorphisms, including the two identified as significant in the prior study. When they examined more specifically a subset of 56 participants with early onset MDD and current depression, they did report some associations of borderline significance with D502–505 in women (4/8 neuropsychological features examined), and with a MDD family history in men. "
[Show abstract][Hide abstract] 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 · 2.24 Impact Factor
"Differences in either rates of melatonin synthesis or signal transduction can lead to the same consequence as an otherwise induced decrease of the hormone. A list of respective gene polymorphisms                                           is presented in Table 2. These polymorphisms have been detected in the genes of the melatonin membrane receptors, MT 1 and MT 2 , of the enzymes of melatonin biosynthesis, AANAT and HIOMT, and also of the orphan receptor GPR50. "
[Show abstract][Hide abstract] ABSTRACT: Melatonin is a pleiotropically acting regulator molecule, which influences numerous physiological functions. Its secretion by the pineal gland progressively declines by age. Strong reductions of circulating melatonin are also observed in numerous disorders and diseases, including Alzheimer's disease, various other neurological and stressful conditions, pain, cardiovascular diseases, cases of cancer, endocrine and metabolic disorders, in particular diabetes type 2. The significance of melatonergic signaling is also evident from melatonin receptor polymorphisms associated with several of these pathologies. The article outlines the mutual relationship between circadian oscillators and melatonin secretion, the possibilities for readjustment of rhythms by melatonin and its synthetic analogs, the consequences for circadian rhythm-dependent disorders concerning sleep and mood, and limits of treatment. The necessity of distinguishing between short-acting melatonergic effects, which are successful in sleep initiation and phase adjustments, and attempts of replacement strategies is emphasized. Properties of approved and some investigational melatonergic agonists are compared.
Aging and Disease 04/2012; 3(2):194-225. · 3.07 Impact Factor
"Specifically, Gpr50 expression in the brain is highly responsive to energy status being decreased by both fasting and high fat diet feeding , 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 , as well as psychiatric affective disorders including bipolar disorder , . "
[Show abstract][Hide abstract] 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.
PLoS ONE 08/2011; 6(8):e23725. DOI:10.1371/journal.pone.0023725 · 3.23 Impact Factor
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