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Pablo V Gejman - One of the best experts on this subject based on the ideXlab platform.

  • synonymous mutations in the human Dopamine Receptor D2 drD2 affect mrna stability and synthesis of the Receptor
    Human Molecular Genetics, 2003
    Co-Authors: Jubao Duan, Mark S Wainwright, Josep M Comeron, Naruya Saitou, Alan R Sanders, Joel Gelernter, Pablo V Gejman
    Abstract:

    Although changes in nucleotide sequence affecting the composition and the structure of proteins are well known, functional changes resulting from nucleotide substitutions cannot always be inferred from simple analysis of DNA sequence. Because a strong synonymous codon usage bias in the human DRD2 gene, suggesting selection on synonymous positions, was revealed by the relative independence of the G + C content of the third codon positions from the isochoric G + C frequencies, we chose to investigate functional effects of the six known naturally occurring synonymous changes (C132T, G423A, T765C, C939T, C957T, and G1101A) in the human DRD2. We report here that some synonymous mutations in the human DRD2 have functional effects and suggest a novel genetic mechanism. 957T, rather than being 'silent', altered the predicted mRNA folding, led to a decrease in mRNA stability and translation, and dramatically changed Dopamine-induced up-regulation of DRD2 expression. 1101A did not show an effect by itself but annulled the above effects of 957T in the compound clone 957T/1101A, demonstrating that combinations of synonymous mutations can have functional consequences drastically different from those of each isolated mutation. C957T was found to be in linkage disequilibrium in a European-American population with the -141 C Ins/Del and Taqi 'A' variants, which have been reported to be associated with schizophrenia and alcoholism, respectively. These results call into question some assumptions made about synonymous variation in molecular population genetics and gene-mapping studies of diseases with complex inheritance, and indicate that synonymous variation can have effects of potential pathophysiological and pharmacogenetic importance.

Enrico Smeraldi - One of the best experts on this subject based on the ideXlab platform.

  • Dopamine Receptor D2 and D3 gene variants are not associated with the antidepressant effect of total sleep deprivation in bipolar depression.
    Psychiatry Research-neuroimaging, 2003
    Co-Authors: Francesco Benedetti, Roberta Lilli, Cristina Lorenzi, Cristina Colombo, Alessandro Serretti, Enrico Smeraldi
    Abstract:

    Total sleep deprivation (TSD) is an effective treatment for mood disorders that is thought to act through an enhancement in several neurotransmitter pathways including Dopaminergic transmission. Genetic factors are likely to play a major role in determining individual differences in TSD response. The aim of this study is to investigate the influence of Dopamine Receptor D3 (DRD3) and Dopamine Receptor D2 (DRD2) variants on TSD antidepressant efficacy in bipolar disorder. One hundred twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were treated with TSD and were genotyped for DRD3 first exon Gly/Ser variants and DRD2 codon 311 Ser/Cys variants using polymerase chain reaction techniques. DRD3 and DRD2 variants were not associated with TSD outcome. Consideration of possible stratification effects such as gender, age at onset and duration of illness did not reveal any association either. The tested gene variants are not a main factor influencing TSD outcome in bipolar disorder.

  • Dopamine Receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses
    Molecular Psychiatry, 2000
    Co-Authors: Alessandro Serretti, Roberta Lilli, Cristina Lorenzi, Enrico Lattuada, Enrico Smeraldi
    Abstract:

    Dopamine Receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses

  • Dopamine Receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses
    Molecular Psychiatry, 2000
    Co-Authors: Alessandro Serretti, Roberta Lilli, Enrico Lattuada, C Lorenzi, Enrico Smeraldi
    Abstract:

    The D2 Receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder ( n = 480), major depressive disorder ( n = 269), schizophrenia ( n = 366), delusional disorder ( n = 44), psychotic disorder not otherwise specified ( n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses.

  • Dopamine Receptor D2 and D4 genes, GABAA alpha-1 subunit gene and response to lithium prophylaxis in mood disorders
    Psychiatry Research-neuroimaging, 1999
    Co-Authors: Alessandro Serretti, Roberta Lilli, Cristina Lorenzi, Linda Franchini, Daniela Di Bella, Marco Catalano, Enrico Smeraldi
    Abstract:

    Abstract Lithium is an effective prophylactic agent in mood disorders, and genetic factors are likely to modulate individual susceptibility to lithium treatment. The aim of this study is to investigate the influence of Dopamine Receptor D2 (DRD2), D4 exon 3 (DRD4), and γ-aminobutyric acid type A (GABA A ) Receptor alpha-1 subunit (GABRA1) gene variants on the efficacy of lithium prophylaxis in mood disorders. Patients with mood disorders ( N =125: bipolar subtype, n =100; major depressive disorder subtype, n =25) were followed prospectively for an average of 53 months and were typed for DRD2 (Ser311/Cys311: n =121, VNTR: n =63), DRD4 ( n =125) and GABRA1 ( n =61) variants using polymerase chain reaction (PCR) techniques. DRD2, DRD4 and GABRA1 variants were not associated with response to lithium. A trend was observed toward a better outcome of DRD4*2/4 subjects, but it was due to only two subjects. Consideration of possible stratification effects like gender, polarity, family history, age at onset and duration of lithium treatment did not reveal any association either. DRD2, DRD4 and GABRA1 variants therefore do not appear to be associated with the outcome of lithium prophylaxis in mood disorders.

  • Dopamine Receptor D2 Ser/Cys311 variant associated with disorganized symptomatology of schizophrenia
    Schizophrenia Research, 1998
    Co-Authors: Alessandro Serretti, Fabio Macciardi, Enrico Smeraldi
    Abstract:

    Abstract The Dopamine D2 Receptor gene has been proposed as a genetic risk factor for schizophrenia ( Arinami et al., 1994 ). However, a number of replications failed to confirm the initial report. The finding of a stronger association considering schizophrenics with the absence of negative symptoms ( Arinami et al., 1996 ) suggested that the influence of DRD2 variants should be analyzed more at the level of symptoms rather than syndromes. One hundred and four inpatients affected by schizophrenia ( n =99) and delusional disorder ( n =5) (DSM IV) were assessed at admission by the Operational Criteria for Psychotic Illness (OPCRIT) and were typed for DRD2 variants using polymerase chain reaction (PCR) techniques. Subjects with the S311C variant presented a higher score on the `Disorganization' factor ( P =0.012). Consideration of possible stratification effects such as sex and age of onset did not reveal any deviation from the whole sample. In conclusion, our preliminary report suggests that the DRD2 S311C variant may be a liability factor for disorganized symptoms among schizophrenics or for a subtype of schizophrenia characterized by highly disorganized symptomatology.

Mainak Sengupta - One of the best experts on this subject based on the ideXlab platform.

  • Potential Role of Brain-Derived Neurotrophic Factor and Dopamine Receptor D2 Gene Variants as Modifiers for the Susceptibility and Clinical Course of Wilson’s Disease
    NeuroMolecular Medicine, 2018
    Co-Authors: Sampurna Ghosh, Sreyashi Bhattacharya, Prasanta Kumar Gangopadhyay, Ashish Bavdekar, Mainak Sengupta
    Abstract:

    Wilson’s disease (WD), an inborn error of copper metabolism caused by mutations in the ATPase copper transporting beta ( ATP7B ) gene, manifests variable age of onset and different degrees of hepatic and neurological disturbances. This complex phenotypical outcome of a classical monogenic disease can possibly be explained by modifier loci regulating the clinical course of the disease. The brain-derived neurotropic factor (BDNF), critical for the survival, morphogenesis, and plasticity of the neurons, and the Dopamine Receptor D2 (DRD2), one of the most abundant Dopamine Receptors in the brain, have been highlighted in the pathophysiology of various neuropsychiatric diseases. This study aims to identify the potential association between BDNF and DRD2 gene polymorphisms and WD and its clinical characteristics. A total of 164 WD patients and 270 controls from India were included in this study. Two BDNF polymorphisms [p.Val66Met (c.G196A) and c.C270T] and the DRD2 Taq1A (A2/A1 or C/T) polymorphism were examined for their association with WD and some of its clinical attributes, using polymerase chain reaction, restriction fragment length digestion, and bidirectional sequencing. The C allele and CC genotype of BDNF C270T were significantly overrepresented among controls compared to WD patients. In addition, a significantly higher proportion of the allele coding for Val and the corresponding homozygous genotype of BDNF Val66Met polymorphism was found among WD patients with age of onset later than 10 years. Furthermore, the A1A1 genotype of DRD2 Taq1A polymorphism was significantly more common among WD patients with rigidity. Our data suggest that both BDNF and DRD2 may act as potential modifiers of WD phenotype in the Indian context.

Bruno Guigas - One of the best experts on this subject based on the ideXlab platform.

  • Research: Genetics Sex-specific effects of naturally occurring variants in the Dopamine Receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility
    2020
    Co-Authors: Bruno Guigas, J. E. De Leeuw Van Weenen, N. Van Leeuwen, A.m.c. Simonis-bik, T. W. Van Haeften, Giel Nijpels, Jeanine J. Houwing-duistermaat, Marian Beekman, Joris Deelen, M. Diamant
    Abstract:

    Aims Modulation of Dopamine Receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic b-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans.

  • Sex-specific effects of naturally occurring variants in the Dopamine Receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.
    Diabetic Medicine, 2014
    Co-Authors: Bruno Guigas, J. E. De Leeuw Van Weenen, N. Van Leeuwen, A.m.c. Simonis-bik, T. W. Van Haeften, Giel Nijpels, Jeanine J. Houwing-duistermaat, Marian Beekman, Joris Deelen, Louis M. Havekes
    Abstract:

    Aims: Modulation of Dopamine Receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. Methods: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. Results: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*10-4) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*10-4) but again not in men (P = 0.34). Conclusion: The present data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene. What's new?: The rs1800497 single nucleotide polymorphism at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women but not in men. The rs6275 single nucleotide polymorphism in the DRD2 gene is associated with increased first-phase glucose-stimulated insulin secretion in women only. Our data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene. © 2014 Diabetes UK. Chemicals/CAS: glucose, 50-99-7, 84778-64-3; insulin, 9004-10-8

  • The Dopamine Receptor D2 agonist bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the α2-adrenergic Receptors in beta cells
    Biochemical Pharmacology, 2010
    Co-Authors: J. E. De Leeuw Van Weenen, Edwin T. Parlevliet, Johannes A. Romijn, Hanno Pijl, Pierre Maechler, Louis M. Havekes, D. M. Ouwens, Bruno Guigas
    Abstract:

    Treatment with the Dopamine Receptor D2 (DRD2) agonist bromocriptine improves metabolic features in obese patients with type 2 diabetes by a still unknown mechanism. In the present study, we investigated the acute effect of bromocriptine and its underlying mechanism(s) on insulin secretion both in vivo and in vitro. For this purpose, C57Bl6/J mice were subjected to an intraperitoneal glucose tolerance test (ipGTT) and a hyperglycemic (HG) clamp 60. min after a single injection of bromocriptine or placebo. The effects of bromocriptine on glucose-stimulated insulin secretion (GSIS), cell membrane potential and intracellular cAMP levels were also determined in INS-1E beta cells. We report here that bromocriptine increased glucose levels during ipGTT in vivo, an effect associated with a dose-dependent decrease in GSIS. During the HG clamp, bromocriptine reduced both first-phase and second-phase insulin response. This inhibitory effect was also observed in INS-1E beta cells, in which therapeutic concentrations of bromocriptine (0.5-50. nM) decreased GSIS. Mechanistically, neither cellular energy state nor cell membrane depolarization was affected by bromocriptine whereas intracellular cAMP levels were significantly reduced, suggesting involvement of G-protein-coupled Receptors. Surprisingly, the DRD2 antagonist domperidone did not counteract the effect of bromocriptine on GSIS, whereas yohimbine, an antagonist of the α2-adrenergic Receptors, completely abolished bromocriptine-induced inhibition of GSIS. In conclusion, acute administration of bromocriptine inhibits GSIS by a DRD2-independent mechanism involving direct activation of the pancreatic α2-adrenergic Receptors. We suggest that treatment with bromocriptine promotes beta cells rest, thereby preventing long-lasting hypersecretion of insulin and subsequent beta cell failure. © 2010 Elsevier Inc.

Terho Lehtimäki - One of the best experts on this subject based on the ideXlab platform.

  • Dopamine Receptor D2 Polymorphism Moderates the Effect of Parental Education on Adolescents' School Performance.
    Mind Brain and Education, 2008
    Co-Authors: Liisa Keltikangas-järvinen, Helle Pullmann, Laura Pulkki-råback, Saija Alatupa, Jari Lipsanen, Nina Airla, Terho Lehtimäki
    Abstract:

    — High parental socioeconomic status is known to have a positive effect on students’ academic achievement. We examined whether variation in the Dopamine Receptor gene (DRD2 polymorphism, rs 1800497) modifies the association between parental educational level and school performance in adolescence. The participants were a randomly selected subsample of individuals participating in the Cardiovascular Risk in Young Finns study (921 girls and 742 boys) aged 12–15 years at the time school performance was assessed. The genotyping was performed using TaqMan 5′'-nuclease assay. A significant interaction was found between childhood parental educational level and students’ DRD2 polymorphism on academic achievement after adjustment for age, gender, household income, parental occupation, maternal nurturance, hyperactivity, and sociability. Parental educational level was significantly positively associated with school achievement in the A2/A2 (n = 1,061) and the A1/A2 (n = 529) genotype groups, but was negative and statistically insignificant in participants carrying the A1/A1 (n = 73) genotype. It is concluded that the extent to which parental education status affects an individual’s academic achievement may be dependent on the individual’s genetic constitution. The findings may increase an acceptance of genetic influence in education, and, consequently, may increase accurateness of educational interventions.

  • Dopamine Receptor D2 gene Taq1A (C32806T) polymorphism modifies the relationship between birth weight and educational attainment in adulthood: 21-year follow-up of the cardiovascular risk in young Finns study
    Pediatrics, 2007
    Co-Authors: Liisa Keltikangas-järvinen, Marko Elovainio, Mika Kivimäki, Olli T. Raitakari, Jorma Viikari, Terho Lehtimäki
    Abstract:

    OBJECTIVE. Low birth weight is suggested to be a risk factor for a wide variety of negative outcomes, including low educational attainment, but the role of cognition-related genetic influences on this association remains unclear. The objective of this study was to study whether variation in the Dopamine Receptor gene (Dopamine Receptor D2 polymorphism, rs1800497) modifies the association between birth weight and educational attainment in adulthood. METHODS. We studied the association between birth weight (range: 1440-4980 g) and educational attainment in 659 men and 832 women aged 27 to 39. Birth weight, gestational age, and parental education were assessed at ages 6 to 18. The genotyping was performed using TaqMan 5' nuclease assay. RESULTS. After adjustment for age, parental education, and gestational age, birth weight was associated with educational attainment in men with A1/A1 or A1/A2 (n = 245) genotype but not in men carrying A2/A2 (n = 414) genotype. In women, no moderating effect of Dopamine Receptor D2 polymorphism was found. CONCLUSIONS. Dopamine Receptor D2 genotype is suggested to modify the association between birth weight and adulthood educational attainment over the whole birth weight range so that carriers of Al allele capitalize on optimal birth weight, whereas a low birth weight seems to be a risk among them. These data support the hypothesis that the effect of birth weight on educational attainment depends on genetic influences. Gender-related difference may refer to an environmental effect (ie, to a better goodness-of-fit between girls' school behaving and expectations of school) that may mask a genetic effect.

  • Dopamine Receptor D2 −141C Insertion/Deletion polymorphism in a Finnish population with schizophrenia
    Psychiatry Research-neuroimaging, 2003
    Co-Authors: Olli Kampman, Terho Lehtimäki, Sami Anttila, Ari Illi, Kari M. Mattila, Markus Roivas, Esa Leinonen
    Abstract:

    Abstract We examined the occurrence of the −141C Ins/Del polymorphism in 93 Finnish patients with schizophrenia. In comparison with previous studies with Japanese and Caucasian populations, the incidence of this polymorphism was unexpectedly low. The findings suggest that the frequency of the −141C Ins/Del polymorphism is lower in Northern Europe compared to other Caucasian and Japanese populations.