D2 Receptor Gene Research Articles

DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia

Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co-expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N=249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (P<0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all P<0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N=368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co-expression was associated with greater prefrontal activity and longer WM reaction times (all corrected P<0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N=87; P<0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information.

Association between Age and the 7 Repeat Allele of the Dopamine D4 Receptor Gene.

Longevity is in part (25%) inherited, and genetic studies aim to uncover allelic variants that play an important role in prolonging life span. Results to date confirm only a few gene variants associated with longevity, while others show inconsistent results. However, GWAS studies concentrate on single nucleotide polymorphisms, and there are only a handful of studies investigating variable number of tandem repeat variations related to longevity. Recently, Grady and colleagues (2013) reported a remarkable (66%) accumulation of those carrying the 7 repeat allele of the dopamine D4 receptor gene in a large population of 90–109 years old Californian centenarians, as compared to an ancestry-matched young population. In the present study we demonstrate the same association using continuous age groups in an 18–97 years old Caucasian sample (N = 1801, p = 0.007). We found a continuous pattern of increase from 18–75, however frequency of allele 7 carriers decreased in our oldest age groups. Possible role of gene-environment interaction effects driven by historical events are discussed. In accordance with previous findings, we observed association preferentially in females (p = 0.003). Our results underlie the importance of investigating non-disease related genetic variants as inherited components of longevity, and confirm, that the 7-repeat allele of the dopamine D4 receptor gene is a longevity enabling genetic factor, accumulating in the elderly female population.

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.

Associations between dopamine D2 receptor gene polymorphisms and schizophrenia risk: a PRISMA compliant meta-analysis.

ObjectiveTo determine the relationships between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia using meta-analysis.MethodThe PubMed, Embase, and China National Knowledge Infrastructure databases were searched to identify relevant literature published up to February 2016. The allele contrast model was used. Stata software was used for statistical analysis, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated to evaluate the associations between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia. Meta-regression and publication bias, trim-and-fill, subgroup, sensitivity, cumulative, and fail-safe number analyses were also performed.ResultsThis meta-analysis included 81 studies. The rs1801028 and rs1799732 were associated with schizophrenia risk among Asians (P=0.04, OR =1.25, 95% CI =1.01–1.55; P<0.01, OR =0.76, 95% CI =0.63–0.92, respectively), while the rs6277 was associated with schizophrenia risk in Caucasians (P<0.01, OR=0.72, 95% CI =0.66–0.79). The rs1800497 was also associated with schizophrenia risk in population-based controls (P<0.01, OR =0.84, 95% CI =0.72–0.97). The rs6275, rs1079597, and rs1800498 were not associated with schizophrenia risk. In addition, meta-regression indicated that the controls may be sources of heterogeneity for the rs1801028 single-nucleotide polymorphism (SNP), while ethnicity may be sources of heterogeneity for the rs6277 SNP. Publication bias was significant for the rs1801028 SNP, and this result changed after the publication bias was adjusted using the trim-and-fill method.ConclusionThis meta-analysis demonstrated that the rs1801028 may be a risk factor for susceptibility to schizophrenia among Asians, while the rs1799732 may be a protective factor for that population. Large-sample studies are necessary to verify the results of this meta-analysis.

The Association of DRD2 with Insight Problem Solving.

Although the insight phenomenon has attracted great attention from psychologists, it is still largely unknown whether its variation in well-functioning human adults has a genetic basis. Several lines of evidence suggest that genes involved in dopamine (DA) transmission might be potential candidates. The present study explored for the first time the association of dopamine D2 receptor gene (DRD2) with insight problem solving. Fifteen single-nucleotide polymorphisms (SNPs) covering DRD2 were genotyped in 425 unrelated healthy Chinese undergraduates, and were further tested for association with insight problem solving. Both single SNP and haplotype analysis revealed several associations of DRD2 SNPs and haplotypes with insight problem solving. In conclusion, the present study provides the first evidence for the involvement of DRD2 in insight problem solving, future studies are necessary to validate these findings.

Interaction between DRD2 variation and sound environment on mood and emotion-related brain activity

Sounds, like music and noise, are capable of reliably affecting individuals’ mood and emotions. However, these effects are highly variable across individuals. A putative source of variability is genetic background. Here we explored the interaction between a functional polymorphism of the dopamine D2 receptor gene (DRD2 rs1076560, G>T, previously associated with the relative expression of D2S/L isoforms) and sound environment on mood and emotion-related brain activity. Thirty-eight healthy subjects were genotyped for DRD2 rs1076560 (G/G=26; G/T=12) and underwent functional magnetic resonance imaging (fMRI) during performance of an implicit emotion-processing task while listening to music or noise. Individual variation in mood induction was assessed before and after the task. Results showed mood improvement after music exposure in DRD2GG subjects and mood deterioration after noise exposure in GT subjects. Moreover, the music, as opposed to noise environment, decreased the striatal activity of GT subjects as well as the prefrontal activity of GG subjects while processing emotional faces. These findings suggest that genetic variability of dopamine receptors affects sound environment modulations of mood and emotion processing.

Gilles de la Tourette syndrome is associated with hypermethylation of the dopamine D2 receptor gene

Several lines of evidence support a “dopaminergic hypothesis” in the pathophysiology of Gilles de la Tourette syndrome (TS). The aim of this study was to investigate for the first time epigenetic changes in DNA methylation in different dopamine genes in adult patients with TS. We included 51 well characterized adult patients with TS (41 males, 10 females, mean age = 35 ± 12.6 years, range, 18–71 years) and compared results with data from a group of 51 sex- and age-matched healthy controls. Bisulfite sequencing was used to measure peripheral DNA methylation of the dopamine transporter (DAT), the dopamine D2 receptor (DRD2), and the catechol-O-methyltransferase (COMT) genes. Compared to healthy controls, patients with TS showed significantly elevated methylation level of the DRD2 gene that positively correlated with tic severity. In contrast, DAT methylation was lower in more severely affected patients. Our results provide evidence for a role of altered epigenetic regulation of dopaminergic genes in the pathophysiology of TS. While DRD2 hypermethylation seems to be directly related to the neurobiology of TS that may lead to dopaminergic dysfunction resulting in enhanced thalamo-cortical movement-stimulating activity, DAT hypomethylation might reflect a secondary mechanism in order to compensate for increased dopaminergic signal transduction due to DRD2 hypermethylation. In addition, it can be speculated that spontaneous fluctuations of tics may be caused by short-term alterations of methylation levels of dopaminergic genes resulting in dynamic changes of tonic/phasic dopaminergic signaling in the striatum and thalamo-cortical output pathways.

The role of C957T, TaqI and Ser311Cys polymorphisms of the DRD2 gene in schizophrenia: systematic review and meta-analysis.

BackgroundThe association between the dopamine D2 receptor (DRD2) gene and schizophrenia has been studied though no conclusive outcomes have been attained. The aim of this study was to perform a systematic review and meta-analysis to explore the relation between three polymorphisms of the DRD2 gene (C957T, TaqI and Ser311Cys) and schizophrenia.MethodsThe search was made in PubMed and EBSCO databases (up to February 2016). The systematic review included 34 case–control association studies (34 for C957T, 16 for TaqI and 36 for Ser311Cys). The association analysis comprised the allelic, additive, dominant, and recessive genetic models. The meta-analysis was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement.ResultsThe meta-analysis showed that TaqI (additive model: OR 0.57, 95% CI 0.30–1.14) and C957T (additive model: OR 0.75, 95% OR 0.58–0.97, recessive model: OR 0.79, 95% CI 0.64–0.98) exert a protective effect against developing schizophrenia. However, the sub-analysis for the C957T variant showed that this polymorphism exhibits a risk factor effect on Chinese individuals (allelic model: OR 1.33, 95% CI 1.04–1.70).ConclusionOur meta-analysis suggests an association of the DRD2 gene and the risk for schizophrenia, given that TaqI and C957T polymorphisms presented a protective effect against schizophrenia, and in the sub-analyses the C957T variant increased the risk for this disorder in the Chinese population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12993-016-0114-z) contains supplementary material, which is available to authorized users.

Dopamine D1and D3Receptors Modulate Heroin-Induced Cognitive Impairment through Opponent Actions in Mice

Background:Chronic abuse of heroin leads to long-lasting and complicated cognitive impairment. Dopamine receptors are critically involved in the impulsive drug-driven behavior and the altered attention, processing speed, and mental flexibility that are associated with higher relapse rates. However, the effects of the different dopamine receptors and their possible involvement in heroin-induced cognitive impairment remain unclear.Methods:The 5-choice serial reaction time task was used to investigate the profiles of heroin-induced cognitive impairment in mice. The expression levels of dopamine D1- and D2-like receptors in the prefrontal cortex, nucleus accumbens, and caudate-putamen were determined. The effects of dopamine receptors on heroin-induced impulsivity in the 5-choice serial reaction time task were examined by agonist/antagonist treatment on D1 or D3 receptor mutant mice.Results:Systemic heroin administration influences several variables in the 5-choice serial reaction time task, most notably premature responses, a measure of motor impulsivity. These behavioral impairments are associated with increased D1 receptor and decreased D3 receptor mRNA and protein levels in 3 observed brain areas. The heroin-evoked increase in premature responses is mimicked by a D1 agonist and prevented by a D1 antagonist or genetic ablation of the D1 receptor gene. In contrast, a D3 agonist decreases both basal and heroin-evoked premature responses, while genetic ablation of the D3 receptor gene results in increased basal and heroin-evoked premature responses.Conclusions:Heroin-induced impulsive behavior in the 5-choice serial reaction time task is oppositely modulated by D1 and D3 receptor activation. The D1 receptors in the cortical-mesolimbic region play an indispensable role in modulating such behaviors.

Genetic variants of dopamine D2 receptor impact heterodimerization with dopamine D1 receptor.

The human dopamine D2 receptor gene has three polymorphic variants that alter its amino acid sequence: alanine substitution by valine in position 96 (V96A), proline substitution by serine in position 310 (P310S) and serine substitution by cysteine in position 311 (S311C). Their functional role has never been the object of extensive studies, even though there is some evidence that their occurrence correlates with schizophrenia. The HEK293 cell line was transfected with dopamine D1 and D2 receptors (or genetic variants of the D2 receptor), coupled to fluorescent proteins which allowed us to measure the extent of dimerization of these receptors, using a highly advanced biophysical approach (FLIM-FRET). Additionally, Fluoro-4 AM was used to examine changes in the level of calcium release after ligand stimulation of cells expressing different combinations of dopamine receptors. Using FLIM-FRET experiments we have shown that in HEK 293 expressing dopamine receptors, polymorphic mutations in the D2 receptor play a role in dimmer formation with the dopamine D1 receptor. The association level of dopamine receptors is affected by ligand administration, with variable effects depending on polymorphic variant of the D2 dopamine receptor. We have found that the level of heteromer formation is reflected by calcium ion release after ligand stimulation and have observed variations of this effect dependent on the polymorphic variant and the ligand. The data presented in this paper support the hypothesis on the role of calcium signaling regulated by the D1-D2 heteromer which may be of relevance for schizophrenia etiology.

Coupling of D2R Short but not D2R Long receptor isoform to the Rho/ROCK signaling pathway renders striatal neurons vulnerable to mutant huntingtin

Huntington's disease, an inherited neurodegenerative disorder, results from abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, invitro, that dopaminergic D2 receptor stimulation acted in synergy with expanded huntingtin to increase aggregates formation and striatal death through activation of the Rho/ROCK signaling pathway. In vivo, in a lentiviral-mediated model of expanded huntingtin expression in the rat striatum, we found that the D2 antagonist haloperidol protects striatal neurons against expanded huntingtin-mediated toxicity. Two variant transcripts are generated by alternative splicing of the of D2 receptor gene, the D2R-Long and the D2R-Short, which are thought to play different functional roles. We show herein that overexpression of D2R-Short, but not D2R-Long in cell lines is associated with activation of the RhoA/ROCK signaling pathway. In striatal neurons in culture, the selective D2 agonist Quinpirole triggers phosphorylation of cofilin, a downstream effector of ROCK, which is abrogated by siRNAs that knockdown both D2R-Long and D2R-Short, but not by siRNAs targeting D2R-Long alone. Aggregate formation and neuronal death induced by expanded huntingtin, were potentiated by Quinpirole. This D2 agonist-mediated effect was selectively inhibited by the siRNA targeting both D2R-Long and D2R-Short but not D2R-Long alone. Our data provide evidence for a specific coupling of D2R-Short to the RhoA/ROCK/cofilin pathway, and its involvement in striatal vulnerability to expanded huntingtin. A new route for targeting Rho-ROCK signaling in Huntington's disease is unraveled with our findings.

Hypothesizing Molecular Genetics of the Holocaust: Were Dopaminergic Genes Involved or Brain Wash?

Numerous studies indicated that the prevalence of certain alleles of the dopamine D2 receptor gene (DRD2) vary across different ethnic groups. Under adverse environmental conditions, these alleles can increase the risk of developing psychiatric symptoms. Thus, we hypothesized that the prevalence of the DRD2 gene Taq IA allele may serve to explain the horrific behaviours practiced by the Nazi regime. Hitler's 'Brain Washing' methods goaded his followers to carry out genocide at a time when carriers of the DRD2 TaqIA allele (the so called 'aggressive--genotype') were significantly higher among the Aryan Germans compared to resident German Jews. It would be of interest, to genotype the Jewish Holocaust survivors, to determine whether those with the Taq AI allele survived in greater numbers. The hypothesis being that, greater survival may result in enhanced frequency of not only the DRD2 AI allele but other reward gene polymorphisms among survivors. Understanding the molecular genetics of any population in terms of reward dependence and subsequent behaviours will be most beneficial in future human interaction whether negative (war) or positive (peace) in nature.

2.47 THE DOPAMINE D4 RECEPTOR GENE, BIRTH WEIGHT, EARLY MATERNAL CARE, MATERNAL DEPRESSION OVER THE POSTNATAL TIME PERIOD, AND THE PREDICTION OF DISORGANIZED ATTACHMENT AT 36-MONTHS OF AGE: A PROSPECTIVE GENE X ENVIRONMENT ANALYSIS

Efforts to understand the developmental pathways for disorganized (D) attachment reflect the importance of D attachment on the prediction of future psychopathology. The inconsistent findings on the prediction of D attachment from the dopamine D4 receptor (DRD4) gene, birth weight, and maternal depression, as well as the evidence supporting early maternal care as a mediator or moderator of more distal environmental effects, suggest the importance of exploring a Gene by Environment model. CorrigendumJournal of the American Academy of Child & Adolescent PsychiatryVol. 56Issue 7PreviewIn New Research Poster 2.47, “The Dopamine D4 Receptor Gene, Birth Weight, Early Maternal Care, Maternal Depression Over the Postnatal Time Period, and the Prediction of Disorganized Attachment at 36-Months of Age: A Prospective Gene x Environment Analysis” by Graffi et al., published in the 2016 Scientific Proceedings supplement to the Journal of the American Academy of Child and Adolescent Psychiatry (2016;10S:S135-S136), coauthor Alexia Jolicoeur-Martineau’s name was misspelled. Full-Text PDF

Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity

Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.

Relationship among methadone dose, polymorphisms of dopamine D2 receptor and tri-dimensional personality questionnaire in heroin-addicted patients.

BackgroundWe investigated whether variation in the dopamine D2 receptor gene (DRD2) and tri-dimensional personality questionnaire (TPQ) scores could be used to aid adjustment of daily methadone requirements of heroin addicts. DRD2 TaqI B polymorphisms and TPQ scores were determined in 138 male Taiwanese heroin addicts who were receiving methadone treatment. Borderline index (harm avoidance + novelty seeking—reward dependence) was calculated for each subject, and three groups were defined: high (mean from all subjects plus 1 standard deviation, or greater), low (half of the calculated high score, or lower) and medium (all values between the high and low scores).ResultsNo significant differences in age (p = 0.60), mean methadone dose (p = 0.75) or borderline index group (p = 0.25) were observed between subjects bearing the B1/B1, B1/B2 and B2/B2 DRD2 TaqI genotypes. Among the individuals with low (≤10), medium (11–20) and high (≥21) borderline index scores, there was a significant difference in mean methadone dose (p = 0.04), but not age (p = 0.90). Further analysis showed that mean methadone dose was significantly higher in subjects with low borderline index scores than in those with high scores (62.5 vs. 47.0 mg/day, p = 0.03). The odds ratio for a daily methadone requirement ≥60 mg (median dose across the 138 subjects) was 2.64-fold greater in the low borderline index group than in the high group (p = 0.04).ConclusionsAlthough the DRD2 TaqI B genotype was not associated with methadone use requirements, borderline index was revealed as a potential predictive marker for the adjustment of methadone dosage requirements in heroin addicts.

Candidate gene study reveals DRD1 and DRD2 as putative interacting risk factors for youth depression.

Alterations in the monoaminergic neurotransmission systems are suspected to be involved in the etiology of neuropsychiatric disorders, including depression. The role of these pathways in the risk of developing depressive symptoms during childhood or adolescence is still not completely clear. This study sought to identify putative genetic factors in genes of serotonergic and dopaminergic systems modulating the level of manifestation of depressive symptoms in children and adolescents. We analyzed 170 single nucleotide polymorphisms (SNPs) in 21 candidate dopaminergic and serotonergic genes in a non-clinical sample of 410 Costa Rican participants of ages between 7 and 18 years, assessing the severity of depressive symptoms through the Child Depression Inventory (CDI). Genotypic and haplotypic associations, as well as epistatic effects, were examined. A significant interaction effect was detected between rs1039089 in conjunction with rs877138 located upstream of the dopamine D1 receptor (DRD1) and the dopamine D2 receptor (DRD2) genes respectively, although no evidence was found for any single variant or haplotype related to a differential liability. This newly described genetic interaction among putative regulatory regions of dopamine receptors could affect the level of manifestation of depressive symptoms through an imbalance of D1-D2 heteromers and modulation of cognitive processes.

Effects of l-Tyrosine on working memory and inhibitory control are determined by DRD2 genotypes: A randomized controlled trial

l-Tyrosine (TYR), the precursor of dopamine (DA), has been shown to enhance facets of cognitive control in situations with high cognitive demands. However some previous outcomes were mixed: some studies reported significant improvements, while other did not. Given that TYR increases DA level in the brain, we investigated, in a double-blind, randomized, placebo-controlled design, whether the C957T genotypes of a functional synonymous polymorphism in the human dopamine D2 receptor (DRD2) gene (rs6277) contribute to individual differences in the reactivity to TYR administration and whether this factor predicts the magnitude of TYR-induced performance differences on inhibiting behavioral responses in a stop-signal task and working memory (WM) updating in a N-back task. Our findings show that T/T homozygotes (i.e., individuals potentially associated with lower striatal DA level) showed larger beneficial effects of TYR supplementation than C/C homozygotes (i.e., individuals potentially associated with higher striatal DA level), suggesting that genetically determined differences in DA function may explain inter-individual differences in response to TYR supplementation. These findings reinforce the idea that genetic predisposition modulates the effect of TYR in its role as cognitive enhancer.

Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis

BackgroundAlthough dopamine D2 receptor antagonists lead to dose-dependent prolactin (PRL) elevations proportionate to their D2 affinity, considerable inter-individual differences exist. We conducted a meta-analytic review of associations between genetic variations in the dopamine D2 receptor gene (DRD2) and PRL levels in antipsychotic-treated subjects. MethodsSystematic literature search (5/8/2015) was performed to find published studies of pharmacogenetic associations between two DRD2 variants, Taq1A (rs1800497) and −141C Ins/Del (rs1799732), and PRL levels during antipsychotic treatment (excluding aripiprazole). Patients were included independent of age or diagnosis. Random effects models were used and Hedges’ g was calculated as the effect size measure. Subgroup analyses explored the effect of sex and diagnosis, (males vs females; schizophrenia vs non-schizophrenia). ResultsAltogether, 11 studies (n=1034, schizophrenia-spectrum=475) for Taq1A polymorphism, and 4 studies (n=451, schizophrenia-spectrum=274) for −141C Ins/Del polymorphism, each reporting on PRL levels but not on the proportion of patients with hyperprolactinemia, were meta-analyzed. Across all patients, there was no statistically significant association between PRL levels and either DRD2 Taq1A genotype or DRD2 −141C Ins/Del genotype. However, in patients with schizophrenia, PRL levels were significantly higher in DRD2 Taq1A A1 carriers than A1 non-carriers (studies=5, n=475, Hedges’ g=0.250, 95% CI=0.068–0.433, p=0.007, I2=0%). DiscussionAlthough there was no significant association between either DRD2 Taq1A genotype or DRD2 −141C Ins/Del genotype and PRL levels in all included patients, our results suggest that DRD2 Taq1A genotype may affect antipsychotic-related PRL levels in patients with schizophrenia. Because of the small sample size, further studies are needed to confirm these results.

Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease: a pharmacogenetic study.

The treatment of early Parkinson's disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinson's disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinson's disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinson's disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in Parkinson symptoms from Weeks 12 to 36 after correction for multiple testing. This is the largest and most comprehensive pharmacogenetics study to date examining clinical response to an anti-parkinsonian drug and the first to be conducted in patients with early stage Parkinson's disease receiving monotherapy. The results indicate a clinically meaningful benefit to rasagiline in terms of the magnitude of improvement in parkinsonian symptoms for those with the favourable response genotypes. Future work is needed to elucidate the specific mechanisms through which these DRD2 variants operate in modulating the function of the nigrostriatal dopaminergic system.media-1vid110.1093/brain/aww109_video_abstractaww109_video_abstract.

Data describing the effect of DRD4 promoter polymorphisms on promoter activity.

This data article tested whether polymorphisms within the dopamine D4 receptor (DRD4) gene promoter can lead to differences in the promoter activity. The variants, a 120-bp variable number tandem repeat (VNTR), −906 T/C, −809 G/A, −616G/C, and −521C/T, were introduced into the DRD4 promoter and the promoter activity was measured in a neural cell line using the luciferase assay. However, no differences were detected among the haplotypes investigated, and the in vitro data obtained from our protocol could not support the involvement of DRD4 promoter polymorphisms in heritable human traits.