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PubMed1996

No association between alcoholism and multiple polymorphisms at the dopamine D2 receptor gene (DRD2) in three distinct Taiwanese populations.

This study examined whether there is evidence for an association between alcoholism and the alleles of the TaqI A, TaqI B, and short tandem repeat polymorphisms (STRP), both individually and as haplotypes, at the dopamine D2 receptor gene (DRD2) in males of three populations from Taiwan. We studied 46 Chinese Han (21 alcoholics and 25 nonalcoholics), 42 Atayal (21 alcoholics and 21 nonalcoholics), and 40 Ami (20 alcoholics and 20 nonalcoholics). Alcoholism was diagnosed according to DSM-III-R criteria and all individuals in the alcoholic groups were severely affected. Significant linkage disequilibrium occurs for the three polymorphic sites in all three populations. No significant association was observed between any of the three polymorphisms at the DRD2 locus, tested individually and as haplotypes, and alcoholism in the three subject groups. We conclude that no association exists between genetic variation at the DRD2 locus and alcoholism in Chinese Han, Atayal, and Ami males.

Adult↗
PubMed2006

P300 development during adolescence: effects of DRD2 genotype.

OBJECTIVE: Young boys at high risk for alcoholism by having a family history of alcoholism (FH+) have lower amplitude of the visual P300 event-related scalp potential. They have also been reported to have a slowing in the rate of P300 amplitude change during adolescence. The present study examined whether the change in P300 amplitude during adolescence in sons of alcoholics and nonalcoholics is affected by D2 dopamine receptor (DRD2) polymorphism. METHODS: P300 was elicited with a visual discrimination task from 71 adolescent sons of alcoholics and social drinkers (Time 1, T1). The task was readministered 2 years later (Time 2, T2). Comparisons were made between boys who had the DRD2 A1 allele (A1+) and boys who did not (A1-), and between boys with one or both parents being alcoholic (FH+) and boys having no alcoholic parents (FH-). RESULTS: Discrimination task accuracy was lowest in the highest risk group (A1+, FH+) at T1, and highest in the lowest risk group (A1-, FH-) at T2, producing a significant interaction of allelic group x family history group x session. Reaction time was faster at T2 than T1, and this effect was larger in FH-boys (125 ms) than FH+boys (40 ms). Overall, the behavioral results suggest mild performance deficits on the discrimination task are associated with higher risk for alcoholism. In both testing sessions, P300 attained larger amplitudes in sons of nonalcoholics than sons of alcoholics. At T2 compared to T1, both the latency and amplitude of the P300 were decreased. However, while the developmental P300 latency effect was equivalent in both the A1+ and A1- allelic groups, the P300 amplitude reduction during adolescence, measured both in response to targets and in target minus non-target subtraction waveforms, was only found in boys with the A1- allele. CONCLUSION: Differences in the developmental course of P300 amplitude over the course of adolescence are dependent on DRD2 polymorphism. SIGNIFICANCE: These results suggest the importance of genetic determinants of the dopaminergic system in understanding the P300 as a risk marker for substance abuse using an integrative developmental perspective.

Adolescent↗
PubMed2006

Association analysis of the dopamine receptor D2 (DRD2) SNP rs1076560 in alcoholic patients.

The dopamine system plays a well-established role in alcoholism. In this study, we examined the association between the single-nucleotide polymorphism (SNP) rs1076560 of the dopamine receptor D2 (DRD2) gene and susceptibility to alcoholism. SNP rs1076560 (C/A) is located in intron 6 of DRD2, where it is 1.4 kb downstream from alternative exon 6 and 83 bp upstream from exon 7. A total of 248 alcoholic patients and 322 healthy controls, all Japanese males, were genotyped for rs1076560 polymorphism by direct sequencing and allele-specific PCR. Data were analyzed using standard chi(2) statistics and a backwards logistic regression approach to adjust for the contribution of aldehyde dehydrogenase-2 (ALDH2) genotype status. The DRD2 risk allele A was more prevalent in the alcoholic patients (40.1%) than in the healthy controls (34.0%) (P=0.034, odds ratio=1.300, 95% confidence interval=1.020-1.657). These data identify SNP rs1076560 as a potentially important variable in the development of alcoholism.

Alcoholism↗
PubMed2002

D(2) dopamine receptor (DRD2) polymorphism is associated with severity of alcohol dependence.

The A(1) allele of the D(2) dopamine receptor (DRD2) gene has been associated with alcohol dependence. However, the expression of this allele risk on the severity of drinking behavior in patients with alcohol dependence has not been systematically explored. The present study examines the association between DRD2 A(1)(+) (A(1)/A(1) and A(1)/A(2) genotypes) and A(1)- (A(2)/A(2) genotype) allele status and key drinking parameters in alcohol-dependent patients. A sample of Caucasian adults was recruited from an alcohol detoxification unit. A clinical interview and the Alcohol Dependence Scale (ADS) questionnaire provided data on consumption, dependence, chronology of drinking and prior detoxification. A(1)(+) allele compared to A(1)- allele patients consumed higher quantities of alcohol, commenced problem drinking at an earlier age, experienced a shorter latency between first introduction to alcohol to the onset of problem drinking and had higher ADS scores. Moreover, A(1)(+) allele patients had more detoxification attempts than their A(1)- allele counterparts. In sum, alcohol-dependent patients with the DRD2 A(1) allele compared to patients without this allele are characterized by greater severity of their disorder across a range of problem drinking indices. The implications of these findings are discussed.

Adult↗
PubMed2005

Molecular genetics support Gray's personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system.

The present study provides the first direct molecular genetics support for Gray's Reinforcement Sensitivity Theory (RST), which is one of the most influential biologically oriented personality theories. It was investigated whether the DRD2 TaqIA and the COMT polymorphisms were related to the dimensions of Gray's personality theory, as measured by the Carver and White BIS/BAS scales. In a sample of 295 healthy subjects results revealed significant DRD2xCOMT interactions (i.e. epistasis) for the total BAS scale (related to positive emotionality) and for the subscales Drive (D) and Fun Seeking (FS). High BAS scores were observed if the catabolic enzyme activity and the D2 receptor density as indicated by the two polymorphisms were in disequilibrium, i.e. in the presence of the Val-/A1- (low enzyme activity/high receptor density) or the Val+/A1+ (high enzyme activity/low receptor density) alleles. In a random subsample (n=48), it could be demonstrated that those allele combinations of COMT and DRD2 associated with high BAS scores also had significantly lower prolactin levels under resting conditions, indicating high dopamine activity, compared to those allele combinations with low BAS scores. Furthermore, two-way interactions of DRD2 TaqIAxsmoking status and of the Met allele of COMTxsmoking status on FS and Metxgender on BIS could be shown.

Adult↗
PubMed2003

Effects of a Drd2 deletion mutation on ethanol-induced locomotor stimulation and sensitization suggest a role for epistasis.

Interpretation of studies using single gene mutants is complicated by possible epistatic interactions with genetic background. Dopamine D2 receptor (Drd2) knockout mice on a C57BL/6 (B6) background show decreased basal locomotion, ethanol preference and ethanol-induced ataxia. Epistatic interactions were studied by examining the effect of this null mutation on several traits on a B6 or 129S6 x 129S2 (129) background. Modification of the null mutant effect on ethanol preference by ethanol-induced locomotor sensitization was also examined in B6 background mice. B6 knockout mice exhibited enhanced ethanol-induced locomotor stimulation and sensitization. The reduced ethanol consumption observed in ethanol-naive B6 Drd2 knockout mice was absent in ethanol-sensitized knockout mice. Ethanol-induced locomotor stimulation was not enhanced in 129 knockout mice, and locomotor sensitization was only modestly increased. However, 129 null mutant mice exhibited reduced basal locomotion and diminished ethanol-induced ataxia, similar to our previous results in B6 mice. The impact of the Drd2 null mutation on a subset of ethanol-related behavioral traits is subject to epistatic influences.

Alcohol Drinking↗
PubMed2001

Polymorphism in exon 6 of the dopamine D(2) receptor gene (DRD2) is associated with elevated blood pressure and personality disorders in men.

A deficient dopamine D(2) receptor (DA2) formation or action may contribute to hypertension via an increase of catecholamine release. In addition, Axis II personality disorders that appears odd or eccentric (cluster A) is associated with a low density of DA2. This study sought to examine if a NcoI restriction fragment length polymorphism (C to T transition) in exon 6 of the dopamine D(2) receptor gene (DRD2) was associated with these characteristics. The genotypes (CC, CT and TT) were compared in anthropometric, endocrine, metabolic and haemodynamic variables as well as estimates of personality disorders in 284 randomly selected 51-year-old men. Homozygotes for the C allele constituted 49% of the men and homozygotes for the T allele 9%, while heterozygotes were 41%. The TT genotype was associated with elevated systolic and diastolic blood pressure, independent of obesity and endocrine abnormalities, including the hypothalamic-pituitary-adrenal axis regulation. Moreover, the TT genotype was significantly more frequent among subjects with grade 1 (mild) hypertension (>140/90 mm Hg) compared to normotensive subjects (<130/85 mm Hg). The polymorphism in exon 6 of the DRD2 was also significantly associated with cluster A personality disorders. These results suggest that a polymorphism in exon 6 of the DRD2examined with the restriction enzyme NcoI is associated with an elevated blood pressure, independent of obesity. Paranoid or schizoid personality disorders is also associated with a polymorphism of the DRD2, which might be associated with a previously demonstrated low density of this receptor.

Alleles↗
PubMed1999

The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder.

The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents was examined in a sample of clinic-referred children and their siblings, and control children and their siblings (n = 236). The contribution of genetic dominance and additivity to mean differences among the A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling. The effect of genetic additivity was statistically significant for both traits in an analysis of all children. The heritability from the DRD2 locus was estimated at 4.27% for hyperactive-impulsive symptoms and 2.12% for inattentive symptoms. Children with the A2A2 genotype had the highest mean level of symptoms. To control for any possible effects of population stratification, this analysis was repeated with parental genotypes as controls. In this smaller sample, although the direction of the effect was the same as that in the whole sample, the genotypic differences failed to reach conventional significance levels and the effect sizes were smaller (h2 = 1.62% and 0.79%, respectively). Furthermore, a genotype relative risk test of children who had questionnaire-based diagnoses of ADHD also failed to yield evidence of either association or linkage. Given that the A1 allele was expected to be the high risk allele, and that results were non-significant in tests that controlled for population heterogeneity, we doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood.

Adolescent↗
PubMed2005

Association of multiple DRD2 polymorphisms with anorexia nervosa.

To investigate whether the dopaminergic system plays a role in the etiology of anorexia nervosa (AN) via the dopamine D2 receptor, we investigated association and transmission disequilibrium at seven single-nucleotide polymorphisms (SNPs) spanning about 75 kbp of the gene DRD2. We studied 191 probands with a DSM-IV diagnosis of AN, 457 parents and affected relatives with a DSM-IV eating disorder diagnosis, and 98 unrelated, female, normal weight controls. The -141 C/- insertion/deletion (-141 Indel), previously shown to affect DRD2 transcription efficiency, and multiple exon seven polymorphisms, one of which has previously been shown to affect DRD2 transcript stability, exhibited statistically significant association with diagnosis in haplotype transmission disequilibrium and in haplotype case : control analyses. Significant linkage disequilibrium between the -141 Indel and two exon seven SNPs (939Y and 957Y) was observed over a distance of >50 kbp in the AN probands but not in the controls. Genetically transmitted variation in D2 dopamine receptor expression mediated by functional polymorphisms affecting transcription and translation efficiency may play a role in vulnerability to AN.

Adolescent↗
PubMed2006

Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials.

Although bupropion and nicotine replacement therapy (NRT) are efficacious tobacco dependence treatments, there is substantial interindividual variability in therapeutic response and most smokers relapse. Pharmacogenetics research may improve treatment outcomes by identifying genetic variants predictive of therapeutic response. We investigated the roles of two functional genetic variants in the dopamine D2 receptor (DRD2) gene in response to pharmacotherapy for tobacco dependence among participants in two randomized clinical trials with a 6-month follow-up period: a double-blind placebo-controlled trial of bupropion (n=414) and an open label trial of transdermal nicotine vs nicotine nasal spray (n=368). At the end of the treatment phase, a statistically significant (p=0.01) interaction between the DRD2 - 141C Ins/Del genotype and treatment indicated a more favorable response to bupropion among smokers homozygous for the Ins C allele compared to those carrying a Del C allele. By contrast, smokers carrying the Del C allele had statistically significantly (p=0.006) higher quit rates on NRT compared to those homozygous for the Ins C allele, independent of NRT type. The C957T variant was also associated (p=0.03) with abstinence following NRT. These results suggest that bupropion may be the preferred pharmacologic treatment for smokers homozygous for the DRD2 - 141 Ins C allele, while NRT may be more beneficial for those who carry the Del C allele. Study findings require confirmation in additional larger samples before they are applied in practice.

Administration, Intranasal↗
PubMedDate not supplied

The dopamine D2 receptor C32806T polymorphism (DRD2 Taq1A RFLP) exhibits no association with smoking behaviour in a healthy UK population.

A single nucleotide polymorphism (SNP) in the Taq1A site near the DRD2 gene has been associated in several studies with smoking behaviour. We genotyped 732 current smokers (241 low, one to nine cigarettes a day, 250 mid, 10-19 cigarettes, 241 high, 20+cigarettes) and 243 never-smokers at this site (C32806T), to test for effects on smoking initiation and amount of tobacco consumed. No significant association between minor allele frequency and smoking status was detected. Multiple regression analysis including DRD2 genotype, sex, age and alcohol consumption as predictors showed that level of cigarette consumption was associated with sex (p=0.003) and age (p=0.002) but not with alcohol consumption (p=0.25) or DRD2 genotype (p=0.76).

Adult↗
PubMedDate not supplied

Alcoholics with the dopamine receptor DRD2 A1 allele have lower platelet monoamine oxidase-B activity than those with the A2 allele: a preliminary study.

Low platelet monoamine oxidase B (MAO-B) activity and the presence of the Taq1 A1 allele of the dopamine D2 receptor (DRD2) gene have independently been proposed as 'biological/genetic' markers for alcoholism. In the present study, the relationship between these two markers was investigated in a group of socially stable Caucasian middle-aged men with a mean (+/-SD) daily ethanol consumption of 85 +/- 57 g. The platelet MAO-B activity was significantly lower in individuals with the DRD2 A1 allele (n = 8), compared to those without it (n = 29). This relationship remained unchanged when including only subjects who fulfilled DSM-IV criteria for alcohol dependence (n = 27). The finding suggests that alcoholics who are carriers of the DRD2 A1 allele may have lower platelet MAO-B activity.

Adult↗
PubMed1980

Structural studies of the lipopolysaccharide from Salmonella typhimurium 902 (ColIb drd2).

Salmonella typhimurium infected with the plasmid ColIb drd2 gave rise to changes in the composition of the bacterial lipopolysaccharide. Bacteria carrying the wild-type ColIb, the revertant of drd2 to the wild type, or the noncolicinogenic strain resulting from the elimination of ColIb drd2, showed no changes in the sugar composition of the lipopolysaccharide. The structure of the O-specific side chains of the lipopolysaccharide produced by S. typhimurium 902, infected with derepressed ColIb mutants has been investigated. As a result of these studies, it is proposed that the O-specific side chains are composed of chemical repeating units with the following structure: (formula: see text).

Carbohydrate Sequence↗
PubMed2006

C957T DRD2 polymorphism is associated with schizophrenia in Spanish patients.

OBJECTIVE: The objective was to confirm whether a homozygous genotype for the C957 allele of the C957T DRD2 gene single nucleotide polymorphism (SNP) is associated with schizophrenia in an independent study population. METHOD: We examined the genotypic distribution of this SNP in a set of clinically ascertained schizophrenic patients (n = 131) and age-matched control subjects (n = 364). Individuals were genotyped using automated analysis of fluorescently labeled PCR products. RESULTS: The distribution of grouped genotypes for the C957T DRD2 SNP (CC vs. CT, TT) showed that C homozygote genotype was over-represented in our patient sample when compared with control subjects. This difference reaches the statistical significance (chi(2) = 7.0; df = 1; P = 0.008; OR = 2.05; % CI 1.2-3.4). CONCLUSION: The findings of this study provide additional evidence that genetic variation at the DRD2 gene plays an important role in the vulnerability to schizophrenia.

Adult↗
PubMed2001

[Dopamine receptor gene (DRD2) polymorphism in patients with endogenous psychoses with regard to their clinical heterogeneity].

Recently an association between genetic dopamine receptor gene (DRD2) polymorphism and schizophrenia was observed in several studies. In the current investigation we attempted to undertake further study of such association using an extended sample which comprised patients with schizophrenia (n = 184), schizoaffective psychosis (n = 63), affective disorders (n = 121)); healthy control subjects (n = 117) and first-degree relatives of the patients with psychoses who show no signs of mental diseases (n = 111). The genotypes A1A1, A1A2 and A2A2 and the relationship between Taq1DRD2 variants and some clinical symptoms and pathogenetic features of the patients with schizophrenia were studied. The results did not confirm the association between DRD2 genotype and any of disorders studied. But the A2A2 genotype frequency in the schizophrenic patient's group, with illness duration above 20 years and highly expressed positive, negative and psychopathological symptoms, increased significantly as compared to control group (73.7% vs 52.9%) and patients with less illness duration (73.7% vs 42.5%). In the latter case odds ratio was calculated as 4.12. In the light of this finding, A2A2 DRD2 genotype appears to be related to chronicity of schizophrenia.

Adult↗
PubMed1995

Evolution of haplotypes at the DRD2 locus.

We present here the first evolutionary perspective on haplotypes at DRD2, the locus for the dopamine D2 receptor. The dopamine D2 receptor plays a critical role in the functioning of many neural circuits in the human brain. If functionally relevant variation at the DRD2 locus exists, understanding the evolution of haplotypes on the basis of polymorphic sites encompassing the gene should provide a powerful framework for identifying that variation. Three DRD2 polymorphisms (TaqI "A" and "B" RFLPs and the (CA)n short tandem repeat polymorphic in all the populations studied, and they display strong and significant linkage disequilibria with each other. The common haplotypes for the two TaqI RFLPs are separately derived from the ancestral haplotype but predate the spread of modern humans around the world. The knowledge of how the various haplotypes have evolved, the allele frequencies of the haplotypes in human populations, and the physical relationships of the polymorphisms to each other and to the functional parts of the gene should now allow proper design and interpretation of association studies.

Base Sequence↗
PubMed1998

A family-based analysis of the association of the dopamine D2 receptor (DRD2) with alcoholism.

The possible association of the DRD2 locus, and in particular the Taql-A1 allele, with alcoholism remains controversial, in part because of differences in allele frequencies among populations. To avoid problems associated with differences in allele frequencies in different populations, we tested whether the DRD2 locus is associated with alcohol dependence in a large family-based sample. Neither the transmission/disequilibrium test nor the Affected Family-Based Controls test provide any evidence of linkage or association between the DRD2 locus and alcohol dependence.

Alcoholism↗
PubMed2002

Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders.

The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.

Adult↗