D2 Receptor Gene Polymorphisms Research Articles

Novel, Replicated Associations Between Dopamine D3 Receptor Gene Polymorphisms and Schizophrenia in Two Independent Samples

Meta-analyses have suggested an association between schizophrenia (SZ) and a coding polymorphism (rs6280/Ser9Gly) at the dopamine D3 receptor gene (DRD3), but results have been inconsistent. Because most studies have evaluated only rs6280, the inconsistencies might reflect associations with other variants. We analyzed polymorphisms spanning 109kb in two independent samples (United States: 13 single nucleotide polymorphisms (SNPs), 331 cases, 151 trios, 274 control subjects; India: 11 SNPs, 141 trios). In the U.S. samples, significant associations were detected with eight SNPs, including rs6280 (p = .001, odds ratio: 1.5). Consistent associations in the case-control and family-based analyses were detected with a common haplotype spanning intron 1 to the 3' region of the gene (rs324029-rs7625282-rs324030-rs2134655-rs10934254; case-control, p = .002; transmission disequilibrium test [TDT], p = .0009; global p-values = .002 and .007, respectively). In the Indian sample, one SNP was associated (rs10934254, p = .03). Moreover, over-transmission of the same common haplotype as the U.S. sample was observed in this cohort (TDT, p = .005; global test, p = .009). Ser9Gly (rs6280) was associated with SZ against this haplotype background but not other haplotypes. These data suggest previous inconsistencies might have resulted from associations with other DRD3 variants. A liability locus might be in linkage disequilibrium (LD) with or carried against, an associated haplotype 3' to rs6280. Comprehensive SNP evaluation in larger samples is needed.

Association between dopamine D4 receptor (DRD4) gene polymorphisms and novelty-elicited auditory event-related potentials in preschool children

We investigated associations of the exon III repeat and the −521 C/T polymorphisms of the DRD4 gene with novelty-elicited auditory ERP components and behavioral resistance to distraction in 57 healthy, typically developing 6-year-old children. Dopamine-related gene polymorphisms have previously been linked to processes directing focused attention. We did not find associations between the 7-repeat allele or the T.7 haplotype and the early ERP responses suggesting that DRD4 polymorphisms did not affect the detection of novelty. However, the same polymorphisms affected the late negative components (LN 1 and LN 2). Late negativities elicited by deviant and novel sounds have been regarded as reflecting reorientation after distraction or additional processing of new information. Children carrying the T.7 haplotype had significantly smaller LN 1 and LN 2 amplitudes. The presence of the T.7 haplotype also significantly enhanced behavioral resistance to distraction. We suggest that less distraction in T.7 carriers led to less reorienting activity (reflected by the LN components). We also speculate that activation of less sensitive and fewer D4 receptors (as with the T.7 haplotype) is less effective in modulating GABAergic inhibitory signaling, which in turn is reflected in smaller LN amplitudes.

Dopamine D2 and D3 receptor gene polymorphisms and clinical outcome of risperidone therapy in schizophrenic patients

The use of SSRIs for the treatment of depression and anxiety in young people is increasing. However, the effects of SSRIs in adolescence, a time when there are substantial changes in neural, cognitive, and social functioning, are not well understood. Here, we review evidence from clinical trials about the benefits and risks of SSRIs in young people and consider their mechanisms of action, as shown through human experimental work and animal models. We emphasise key outstanding questions about the effects of SSRIs in youth, identified through gaps in the literature and in consultation with young people with lived experience. It is crucial to characterise the mechanisms underpinning risks and benefits of SSRIs in this age group to progress the field, and to narrow the chasm between the widespread use of SSRIs in youth and the science on which this use is based.

Association study of dopamine D2 and D3 receptor gene polymorphisms with cocaine dependence

Genetic factors play a role in the vulnerability to cocaine dependence. The reinforcing properties of cocaine are related to the dopaminergic system, and, in particular, the dopamine receptors have been linked to the reward mechanisms. The present study examines the role of the variants TaqI A of the dopamine D2 receptor gene and BalI of the dopamine D3 receptor gene in a Brazilian sample consisting of 730 cocaine dependents and 782 healthy controls. The studied polymorphisms did not show any difference in allelic frequencies or genotypic distribution between the groups. Our data do not support a role for the dopamine D2 receptor gene TaqI A and dopamine D3 receptor gene BalI gene polymorphisms in the susceptibility to cocaine dependence in a Brazilian sample.

Preprohypocretin Polymorphisms in Parkinson Disease Patients Reporting “Sleep Attacks”

Previously, we found a significant association between the dopamine D2 receptor gene polymorphism Taq IA and sudden onset of sleep in patients with Parkinson disease. Here we evaluated the association between the preprohypocretin (-909T/C), (-22C/T), and (-20C/A) polymorphisms and sudden onset of sleep in the same population of patients with Parkinson disease. We conducted an association study analyzing the distribution of preprohypocretin polymorphisms in Germanic, caucasian Parkinson disease patients with and without sudden onset of sleep, matched according to drug therapy, disease duration, sex, and age. Movement disorders section at a university hospital. 132 Parkinson disease patients with sudden onset of sleep and 132 Parkinson disease patients without sudden onset of sleep. Blood samples were taken from each participant and used for DNA extraction. Polymorphisms were analyzed by established polymerase chain reaction protocols or direct sequencing. The variant allele T of the (-909T/C) preprohypocretin polymorphism was more commonly found in Parkinson disease patients with sudden onset of sleep. Statistical analysis showed that there were significant differences in the genotype (P = .024) and allele (P = .018) distribution between both groups. For heterozygous and homozygous carriers of allele T, the genotype relative-risk estimates for the presence of sudden onset of sleep were 2.01 (95% confidence interval: 0.76-5.34) and 2.81 (95% confidence interval: 1.09-7.25), respectively. Our results show a significant association between the (-909T/C) preprohypocretin polymorphism and sudden onset of sleep in Parkinson disease. However, we could not demonstrate any interaction between the Taq IA and (-909T/C) polymorphisms with respect to the occurrence of sudden onset of sleep, suggesting that multiple genetic factors may contribute to the pathogenesis of this phenomenon.

Association between neuroleptic drug-induced extrapyramidal symptoms and dopamine D2-receptor polymorphisms in Japanese schizophrenic patients

The aim of the present study is to examine the relationship between dopamine D2-receptor gene (DRD2) polymorphisms (Taq1A, Taq1B, -141C Ins/Del) and the risk of extrapyramidal adverse effects (EPS), assessed according to the Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), or the maintenance dose of antipsychotics in schizophrenic patients. The DIEPSS score was significantly higher in patients bearing the -141C Del allele than in those without it. Taq1A and Taq1B restriction fragment length polymorphisms (RFLPs) did not significantly affect the DIEPSS score. On the other hand, maintenance doses of neuroleptics and antiparkinsonian drugs were significantly higher in patients with the B1 allele of Taq1B RFLP than in those without it, while the Taq1A RFLP and -141C Ins/Del polymorphisms were not significantly related to the maintenance doses. In conclusion, the risk of EPS may be increased in patients with the -141C Del allele of the DRD2 gene. In these patients, antipsychotics should be administered with caution.

Association analysis of dopamine D4 receptor gene polymorphism with ADHD and related symptomatology

目的 探讨多巴胺D4受体(dopamine D4 receptor,DRD4)基因 48 bp可变重复序列(variant number tandem repeat ,VNTR)多态性与注意缺陷多动障碍(Attention-deficit hyperactivity disorder,ADHD)及其相关症状的关系.方法取139例ADHD患者及115例正常对照,利用Achenbach父母用儿童行为调查表(Child Behaviour Checklist,CBCL)来评定患者的临床症状;采用聚合酶链式反应(polymerase chain reaction,PCR)、聚丙烯酰胺凝胶电泳结合银染技术,检测ADHD患者和对照组基因型和等位基因的频率.结果患者组和对照组DRD4基因型和等位基因的频率与对照组相比无显著性差异(P >0.05).DRD4基因的携带5等位基因(DRD4*5+)组个体间焦虑/抑郁(5.1±4.0)和内化性(12.1±7.6)两分量表分和非携带5等位基因(DRD4*5-)组个体间焦虑/抑郁(2.7±2.7)和内化性(7.3±5.4)两分量表分有显著性差异(Mann-Whitney Z=1.982,P =0.047;Z=2.047,P =0.041),DRD4*5+基因型个体焦虑/抑郁和内向性两行为分量表评分高.而其它分量表及行为总分无显著性差异.结论本研究未发现DRD4基因48 bp VNTR多态性与ADHD存在关联,但DRD4基因48 bp VNTR多态性与ADHD伴内化问题可能有关。

Disconnection and Cognitive Dysmetria in Schizophrenia

Disconnection and Cognitive Dysmetria in Schizophrenia

Dopamine D4 receptor gene and attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder is a prevalent disorder characterized by hyperactivity, impulsivity, and attentional dysfunction. It is familial and heritable. Its pathophysiology is thought to involve an abnormality of the brain's dopaminergic neurotransmitter system. Recent work has identified a distinct polymorphism of the dopamine D4 receptor gene in normal people with a behavioral temperament profile characterized by features of "novelty seeking" which include impulsive and exploratory behaviors. These personality traits are also characteristic of children with attention deficit hyperactivity disorder, especially the hyperactive-impulsive type. This study investigated the relationship between dopamine D4 receptor gene polymorphism, temperament categories, and attention deficit hyperactivity disorder in 81 children with the disorder and 24 control subjects. There was no significant association between dopamine D4 receptor gene alleles, Novelty Seeking traits, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of attention deficit hyperactivity disorder--Hyperactive impulsive type or Inattentive type.

No association of the dopamine D4 receptor (DRD4) and -521 C/T promoter polymorphisms with infant attachment disorganization

In a first molecular genetic study Lakatos and colleagues found an association between attachment disorganization and the dopamine D4 receptor (DRD4) gene polymorphism, in particular in the presence of the -521 T allele in the promoter region of the DRD4 gene. Replication of their study in a sample of 132 infants did not confirm the role of the DRD4 7+ -allele and the -521C/T promoter gene in disorganized attachment. Although our sample was larger, and contained more children with CT or TT alleles, which enhanced the probability of finding the DRD4 and C/T interaction, the association was not found. Even when we combined our sample with the Lakatos sample, the interaction effect of the DRD4 and -521 C/T polymorphisms on disorganized attachment was absent.

Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population

There are several lines of evidence implicating the dopamine D3 receptor in the pathophysiology of schizophrenia. The Ser9Gly polymorphism of the dopamine D3 receptor gene ( DRD3) has been the most extensively investigated DRD3 variant in connection with the disease but results have been inconclusive. Recent reports indicate that the Ser9Gly polymorphism is in linkage disequilibrium with other markers, but association studies between DRD3 haplotypes and schizophrenia have had mixed results. Genetic heterogeneity may be one of the causes of contradicting results. In order to clarify the role of DRD3 alterations in the aetiology of disease, we have investigated three D3 genetic variants (Ser9Gly, −205-G/A, −7685-G/C) in a sample of patients with schizophrenia or schizoaffective disorder ( N=118) and controls ( N=162) recruited from a human isolate from Navarra (Northern Spain) of Basque origin. Although no association was found between the Ser9Gly or the −205-A/G polymorphisms and disease, an excess of allele −7685-C was observed in patients ( p=0.002 after correction for multiple analyses). Haplotype analysis shows the three markers to be in strong linkage disequilibrium ( p<0.0001) and strongly associated with disease ( p<1×10 −5). These results may suggest that these polymorphisms exert a combined or synergistic effect on susceptibility to schizophrenia, or are in linkage with an unknown causative factor. However, further replication in independent samples is required.

Dopamine receptor gene polymorphisms in Parkinson's disease patients reporting "sleep attacks".

Genes encoding proteins involved in dopaminergic transmission are potential candidate genes for the induction of somnolence in Parkinson's disease (PD) because dopaminergic agents have been shown to be associated with sudden onset of sleep (SOS) in PD. We conducted an association study on dopamine D2, D3, and D4 receptor gene polymorphisms comparing 137 PD patients with SOS and 137 PD patients without SOS matched according to drug therapy, disease duration, sex, and age. Our results show a significant association between the dopamine D2 receptor gene polymorphism Taq IA and SOS in PD. No significant association between two other investigated polymorphisms and the phenomenon of "sleep attacks" in PD was observed.

Association Study of Catechol- O-Methyltransferase Gene and Dopamine D4 Receptor Gene Polymorphisms and Personality Traits in Healthy Young Chinese Females

Human personality traits, which are substantially heritable, may be modulated by monoamine neurotransmitters. It has been demonstrated that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect monoamine metabolism, is possibly associated with specific personality traits. In addition, a polymorphism in the dopamine D₄ receptor (DRD4) gene exon 3 has been associated in some, but not all, studies with the novelty seeking personality trait, as evaluated by the Tridimensional Personality Questionnaire (TPQ). In this study, associations between these two polymorphisms and TPQ personality traits were investigated in a sample population of 120 healthy young Chinese females. The results of this analysis reveal that the COMT Val158Met polymorphism was significantly associated with novelty seeking (p = 0.017) and reward dependence scores (p = 0.015) in our sample. However, no significant differences were demonstrated comparing TPQ-specific scores for subjects bearing different DRD4 genotypes. The present study suggests that the functional COMT Val158Met genetic polymorphism contributes to individual differences in the personality traits novelty seeking and reward dependence. Similar to the results of a recent meta-analytic review, however, no association was demonstrated between this DRD4 polymorphism and novelty seeking in our young Chinese female sample population.

Gene–environment interaction in hyperkinetic conduct disorder (HD + CD) as indicated by season of birth variations in dopamine receptor (DRD4) gene polymorphism

Recently, an interaction between season of birth and the expression of candidate genes has been suggested. Season of birth variations in tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR) and the dopamine D4 receptor (DRD4) gene polymorphisms are different for affective disorders and schizophrenia. The DRD4 gene has been postulated as a candidate gene for attention-deficit-hyperactivity disorder (ADHD), equivalent to hyperkinetic disorder (HD). The seven-repeat long variant of this gene (DRD4*7) in comparison to the short repeat variants of the DRD4 gene polymorphism, has been found to be associated with ADHD. A seasonal pattern of birth has also been proposed for different subtypes of ADHD. Therefore, in a subgroup of children with HD and conduct disorder (CD) and in healthy controls, we investigated a possible association between the DRD4*7 allele and HD + CD in association with the season of birth. Supporting this hypothesis, we found an interaction between the seasons of birth and the expression of the DRD4 candidate gene in children with HD + CD as well as in controls, which differ significantly from each other. Depending on the season of birth, children carrying the DRD4*7R allele showed different relative risks for developing HD + CD.

Association study of dopamine D2, D3, D4 receptor and serotonin transporter gene polymorphisms with sleep attacks in Parkinson's disease.

Association study of dopamine D2, D3, D4 receptor and serotonin transporter gene polymorphisms with sleep attacks in Parkinson's disease.

Dopamine D3 receptor gene polymorphisms, blood pressure and nephropathy in type 1 diabetic patients.

Dopamine modulates blood pressure in the kidney. The aim of this study was to investigate whether two previously known (-707 G/C, Ser9Gly) and one novel (Ala17Ala) polymorphism in the dopamine D3 receptor gene and/or their haplotypes are associated with blood pressure, diabetic nephropathy or renal variables in the study subjects. A cross-sectional, case-control study with a total of 996 type 1 diabetic patients from the multicentre, nationwide FinnDiane Study. Patients were recruited consecutively and classified into four groups according to their renal status. The frequencies of the genotypes harbouring the minor allele were 33, 51 and 19% for the -707 G/C, Ser9Gly and Ala17Ala polymorphisms, respectively. Frequencies of the -707 G/C minor genotypes were 35 (normoalbuminuria), 32 (microalbuminuria), 28 (proteinuria) and 39% (end-stage renal disease) (chi(2) = 6.3, df = 3, P = 0.1), of the Ser9Gly 52, 51, 46 and 57% (chi(2) = 6.3, df = 3, P = 0.1) and of the Ala17Ala polymorphism 18, 19, 19 and 21% (chi(2) = 0.7, df = 3, P = 0.9), respectively. Five haplotypes were identified, but no differences were seen between those with and without diabetic nephropathy. Furthermore, there were no differences in blood pressure levels nor in any renal variables between genotypes or haplotypes. These results do not provide evidence for an involvement of the dopamine D3 receptor gene in blood pressure levels or in the pathogenesis of diabetic nephropathy in type 1 diabetic patients.

No evidence of association or linkage disequilibrium between polymorphisms in the 5' upstream and coding regions of the dopamine D4 receptor gene and schizophrenia in a Portuguese population.

Alterations in dopaminergic system have been implicated in the pathophysiology of this disease for many years, and this study was performed to assess the possible involvement of the dopamine D4 receptor (DRD4) gene polymorphisms either in the 5' upstream or in the coding regions, in the etiology of schizophrenia. The approach included an association study with 90 Portuguese trios by doing the analysis of the individual alleles and the haplotypes. For the polymorphisms in the 5' upstream region (-C616G and -C521T) and in the coding region (48 bp repeat) of the DRD4 gene, negative results were obtained with both haplotype relative risk (HRR) and transmission disequilibrium test (TDT), as well as transmit. These data suggest that polymorphisms (-C616G, -C521T, and 48 bp repeat) at the DRD4 gene do not have a minor effect in the susceptibility to schizophrenia in our sample.

Dopamine D2 (DAD2) and dopamine D3 (DAD3) receptor gene polymorphisms and treatment outcome in alcohol dependence.

The dopaminergic system is critically involved in reward mechanisms mediating the reinforcing effects of alcohol. The intention of this study was to investigate the genotypic frequencies of the -141C Ins/Del polymorphism of the DAD2 receptor gene as well as the Bal I polymorphism of the DAD3 receptor and their potential association with treatment outcome in alcoholism. Therefore, individuals suffering from primary alcohol dependence were clinically and genetically characterized and followed prospectively over a period of one year after inpatient treatment. No association was found between DAD2 or DAD3 receptor gene variants and treatment outcome as reflected by abstinence/relapse after one year. Taking into account potential stratification effects, such as family history, gender, age of onset, or severity of the disease an association with DAD2 or DAD3 gene variants could neither be found. In conclusion, we found no evidence that the DAD2 or DAD3 gene variants investigated have a major influence on treatment outcome in primary alcohol dependence.

D2 and D4 dopamine receptor gene polymorphisms and personality traits in a young Korean population.

The correlation between the D4 dopamine receptor gene (DRD4) and the D2 dopamine receptor gene (DRD2) polymorphisms was investigated with personality traits. For this study, homogeneous population consisting of 243 young alcohol- and drug-naive Koreans who were blood-unrelated with a mean age (+/-SD) of 13.87 (+/-0.30) years old was analyzed for the DRD4 and the DRD2 polymorphisms with their personality trait by Temperament and character inventory (TCI). The association between Novelty seeking (NS) score and DRD4 long alleles was only observed among the female subjects (t = 2.11, P = 0.037), but not in the male counter part. Female subjects who carried the DRD2 less frequent alleles (TaqI A1, TaqI B1, and Intron6 1) showed higher RD4 scores (dependence vs. independence) of Reward dependence (RD) than those without these alleles (P < 0.05). There was no interaction between DRD4 and DRD2 on the personality traits. These results, thus, confirmed the previous findings in which the long repeats of the DRD4-exon III polymorphism are related to NS personality trait, and also suggested that the DRD2 less frequent alleles were also associated with the reward-dependent trait.

Dopamine D3 receptor gene polymorphism and violent behavior: relation to impulsiveness and ADHD-related psychopathology.

Several lines of evidence indicate that dopaminergic neurotransmission is involved in the regulation of impulsive aggression and violence and that genetically determined variability in dopaminergic gene expression modifies complex traits including that of impulsivity and aggression. In this study we report an association of the dopamine D3 receptor (DRD3) polymorphism with impulsiveness according to Eysenck's EIQ and scores on the German short version of the Wender Utah Rating Scale (WURS-k), which we used for the assessment of a history of ADHD-related symptoms. This association was detected in a group of violent offenders, but not in non-violent individuals. Highest scores of EIQ impulsiveness and of the WURS-k were found in heterozygous violent individuals, while homozygotes showed significant lower rating scores, suggesting an heterosis effect. The results of our study suggest that variations of the DRD3 gene are likely involved in the regulation of impulsivity and some psychopathological aspects of ADHD related to violent behavior.