Dopamine D2 Receptor Gene Polymorphisms Research Articles

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.

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.

Combination of dopamine D2 receptor gene polymorphisms as a possible predictor of treatmentresistance to dopamine receptor antagonists in schizophrenic patients

Combination of dopamine D2 receptor gene polymorphisms as a possible predictor of treatmentresistance to dopamine receptor antagonists in schizophrenic patients

A dopamine D2 receptor gene polymorphism and physical activity in two family studies

A role for dopamine neurotransmission in the regulation of motor activity and reinforcement of behavior is supported by considerable evidence. We studied the association between a marker in the dopamine D2 receptor gene (DRD2) and physical activity level in two cohorts. A first cohort consisted of 721 participants from 161 families of the Quebec Family Study (QFS). Physical activity phenotypes were obtained from a three-day diary and a questionnaire probing physical activity during the past year. The second cohort was the HERITAGE Family Study (HERITAGE), which included 275 Black and 497 White participants from 228 families, among whom past year leisure time and occupational physical activity were probed. A fragment length polymorphism in exon 6 of the DRD2 gene was detected by the polymerase chain reaction (PCR) and NcoI digestion. Frequencies for the T and C alleles were 28% and 72% in the QFS. In the QFS, TT homozygote women had 25% and 34% lower age and BMI-adjusted physical activity level during the past year, compared to CC homozygotes and CT heterozygotes ( F=4.42, P=.016). The DRD2 genotype was not associated with the QFS phenotypes obtained from the three-day diary. In the HERITAGE, the frequency of the T allele was 30% among Whites and 63% among Blacks. Similarly, the TT homozygote White women had 29–38% lower sports index ( F=4.09, P=.023) and 27–33% lower work index ( F=6.23, P=.004) than the CC homozygotes and CT heterozygotes. The results suggest that DNA sequence variation in the DRD2 gene is associated with physical activity levels among White women.

Dopamine D 4 receptor gene polymorphism and extraversion revisited: results from the Munich gene bank project for alcoholism

In 1998 a gene bank project for association studies in alcoholism was initiated at the Psychiatric Hospital of Munich. The research instruments used were partly adopted from the US collaborative study of the genetics of alcoholism and include the family history assessment module (FHAM), the semi-structured interview for assessment of genetics in alcoholism (SSAGA) and a number of personality inventories such as the Zuckerman's sensation-seeking scale, the NEO Five factor inventory and the temperament and character inventory. Based on the examination of 181 alcoholic subjects, no association was found between Dopamine D4 receptor gene polymorphism and novelty-seeking or extraversion as assessed by the three personality inventories. These findings are in line with a number of more recent studies questioning the association between novelty-seeking and DRD4 dopamine receptor gene polymorphism. Possible implications of these findings are discussed.

Effects of dopamine D 4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions

Dopamine D4 receptor gene polymorphism has been repeatedly associated with attention deficit hyperactivity disorder (ADHD) and related personality traits. We recently reported that motor hyperactivity in an animal model of ADHD was dose-dependently reversed by CP-293,019, a D4 receptor-selective antagonist. However, behavioral effects of this agent may not be attributed exclusively to D4 receptor blockade, since it interacts with other sites including serotonin receptors. To test further the hypothesis that D4 receptor blockade can reduce motor hyperactivity, behavioral effects of three chemically and pharmacologically dissimilar D4 antagonists were compared to that of ketanserin, a serotonin 5-HT(2A/2C) antagonist. Selective dopamine lesions were made in male rats at postnatal day (PD) 5 with intracisternal 6-hydroxydopamine (100 microg) after desipramine pretreatment (25 mg/kg, SC) to protect noradrenergic neurons. Effects of D4 receptor-selective antagonists and ketanserin on lesion-induced motor hyperactivity were examined during the periadolescent period (postnatal days 23-26) with an infrared photobeam activity system. The D4 antagonists L-745,870 and U-101,958 dose-dependently inhibited motor hyperactivity in rats with neonatal lesions, whereas S-18126 lacked this effect at doses up to 30 mg/kg. None of these drugs affected motor behavior in sham control rats. In contrast, ketanserin produced apparent sedative effects in both lesioned and intact control rats without normalizing hyperactivity. Motor hyperactivity in this ADHD model was selectively antagonized by three of four dopamine D4 receptor antagonists evaluated, encouraging clinical assessment of D4 antagonists in patients with ADHD.

Lack of association of dopamine D4 receptor gene polymorphisms with ADHD subtypes in a population sample of twins.

Attention-deficit hyperactivity disorder (ADHD) is a common, highly heritable syndrome of childhood characterized by problems with inattention, hyperactivity, and impulsivity. A variety of case control and family-based transmission distortion genetic studies of ADHD have focused on the possible involvement of polymorphisms of the DRD4 receptor gene. The majority of studies have examined the association of variously defined ADHD with an exon 3 polymorphism containing a variable number of imperfect 48 base pair repeats. Recently, McCracken et al. [2000: Mol Psych 5:531-536] reported an association of the DSM-IV primarily inattentive ADHD subtype with a 5' 120 base pair repeat polymorphism in the DRD4 gene. In this report, we test for the possible association of these two polymorphisms with population-derived samples of DSM-IV ADHD subtypes. Furthermore, we extend previous studies by testing for associations with ADHD subtypes derived from latent-class analysis of interview responses. In contrast to most, but not all, previous studies, we failed to demonstrate any significant association of the exon 3 7-repeat allele with ADHD. Nor did we replicate the association of the 5'120 base pair repeat polymorphism. We do find a significant association of the exon 3 3-repeat allele with a novel talkative/impulsive latent-class-defined subtype of ADHD.

Association analysis between two functional dopamine D2 receptor gene polymorphisms and schizophrenia.

The dopamine D2 receptor (DRD2) gene has been listed as one of the candidate genes for susceptibility to schizophrenia. To date, a significant association between schizophrenia and two functional DRD2 gene polymorphisms, Ser311Cys and -141C Ins/Del, in Japanese samples, has been reported by Arinami et al. [1994: Lancet 343:703-704; 1997: Hum Mol Genet 6:577-582]. In the present study, we replicated the findings of Arinami et al. [1994: Lancet 343:703-704; 1997: Hum Mol Genet 6:577-582] in the same ethnic groups (Japanese samples) with the same polymorphisms (Ser311Cys and -141C Ins/Del). We genotyped these two polymorphisms for 241 patients and for 201 controls. Neither polymorphism was associated with schizophrenia. Moreover, in a haplotype analysis of the present sample, combined pairs of two polymorphisms provided no evidence for the association of either haplotype with schizophrenia. Our findings indicate that an association between the two functional DRD2 gene polymorphisms, Ser311Cys and -141C Ins/Del, and schizophrenia is unlikely.

Dopamine D4 receptor gene polymorphism and personality traits in healthy volunteers.

An association between long alleles of a variable number tandem repeat (VNTR) polymorphism in the dopamine receptor D4 gene and the extraversion related personality traits Excitement and Novelty Seeking has been reported in healthy subjects. In an attempt to replicate the previous findings, 256 healthy Caucasian volunteers were analysed for a potential relationship between the dopamine receptor D4 exon III VNTR polymorphism and Extraversion as assessed by the Revised Neo Personality Inventory (NEO PI-R). The present study did not yield evidence for an association between Extraversion and the dopamine receptor D4 polymorphism.

Modulation of blood pressure and obesity with the dopamine D2 receptor gene TaqI polymorphism.

Pharmacological data suggest that obesity and blood pressure (BP) may be modulated through the dopamine D2 receptor (DD2R), which may represent an underlying mechanism that links these conditions. A TAQ:I polymorphism near the DD2R gene has been associated with indices of obesity in white populations. We compared anthropometric and fasting plasma biochemical parameters between 209 nondiabetic hypertensive and 174 gender-matched normotensive Chinese subjects. The hypertensives had increased dyslipidemia, increased fasting plasma glucose concentrations, and a greater degree of obesity. The A1 and A2 alleles of the DD2R gene TAQ:I polymorphism were identified with a polymerase chain reaction-based restriction fragment length polymorphism protocol. The A1 allele frequency was decreased in the hypertensives (42.0%) compared with the control subjects (52.0%, P=0.006), and genotype frequencies were different (P=0.05) between the 2 groups. In the combined population (n=383), systolic, diastolic, and mean arterial BPs were 6, 5, and 6 mm Hg lower, respectively, in subjects with the A1A1 genotype relative to the A2A2 genotype (all P<0.05), whereas skinfold thickness was increased at the iliac (P<0.001) and triceps (P<0.03) sites but not at the biceps or subscapular sites. Furthermore, this DD2R gene polymorphism was shown to be a significant independent predictor of diastolic BP and iliac and triceps skinfold thicknesses (all P<0.03). These contrasting associations of the DD2R TAQ:I polymorphism A1 allele with lower BP but increased markers of "gynoidal" or peripheral subcutaneous obesity (iliac and triceps skinfold thicknesses) in our Chinese population may provide some insight into the underlying relationship between BP and body fat distribution, but the exact nature of this link remains to be determined.

Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD.

To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD. Peak-dose dyskinesias are the most common side effects of levodopa therapy for PD. The identified predictors may only partially account for the risk of developing peak-dose dyskinesias because a substantial proportion of patients never develop peak-dose dyskinesias. Genetic factors could play a role in determining the occurrence of peak-dose dyskinesias. A case-control study of 136 subjects with sporadic PD and 224 population control subjects. We studied three polymorphisms involving the dopamine receptor D1 gene and one intronic short tandem repeat polymorphism of the dopamine receptor D2 gene. The polymorphisms of the dopamine receptor D1 gene were not associated with the risk of developing PD or peak-dose dyskinesias. The 15 allele of the polymorphism of the dopamine receptor D2 gene was more frequent in parkinsonian subjects than in control subjects. More important, the frequency of both the 13 allele and the 14 allele of the dopamine receptor D2 gene polymorphism was higher in nondyskinetic than in the dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least 1 of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. Certain alleles of the short tandem repeat polymorphism of the dopamine receptor D2 gene reduce the risk of developing peak-dose dyskinesias and could contribute to varying susceptibility to develop peak-dose dyskinesias during levodopa therapy.

Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia

Genetic factors and dopamine receptor dysfunction have been implicated in the pathophysiology of schizophrenia. Recently, an association between a putative functional promoter polymorphism (−141C Ins/Del) in the dopamine D2 receptor gene and schizophrenia was reported. We investigated unrelated Swedish schizophrenic patients ( n=129) and control subjects ( n=179) for the same polymorphism. Similarly to a previous Japanese report, the −141C Del allele frequency was significantly lower in patients than controls (χ 2=4.4, 1 df, p<0.05; odds ratio 0.49, 95% confidence interval 0.26–0.91). The present and previous results may indicate that the −141C Ins/Del dopamine D2 receptor gene polymorphism affects susceptibility to schizophrenia.

Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers.

The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. This variability might be due to genetic or environmental factors. In the present analysis we searched for relationships between dopamine D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density in vivo, as measured by positron emission tomography and [11C]raclopride in 56 healthy subjects. There was a significant association between presence of a putative functional DRD2 promoter allele (-141C Del) and high striatal dopamine receptor density (t= 2.32, P= 0.02). In agreement with some previous studies the presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t=2.58, P=0.01). Also the DRD2 TaqIB1 allele was associated with low dopamine receptor density (t= 2.58, P= 0.01) wheras there was no significant relationship between another common silent intronic DRD2 short tandem repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results suggest that DRD2 genotypes may participate differentially in the regulation of striatal dopamine D2 receptor density in healthy human subjects. The results should be interpreted with caution because of the limited sample size.

Lack of association of the dopamine D4 receptor gene polymorphism with alcoholism in a Brazilian population

The dopaminergic system has been implicated in alcoholism, but most of the past investigations concentrated on the dopamine D2 receptor (DRD2), with conflicting results. The dopamine D4 receptor gene (DRD4) is in the same class as DRD2, but presents different pharmacological properties. This gene has an expressed highly variable 48 base pair (bp) tandem repeat polymorphism (VNTR), which could be of functional relevance.We screened 100 Caucasians and 100 Afro-Brazilians to determine the allele distribution of this polymorphism in a southern Brazilian population. The allele frequencies observed are significantly different from those described in the literature except when Afro-Brazilians and African Bantus are compared. A group of 136 male alcoholics, classified according to DSM-III-R criteria for alcohol dependence, was also ascertained. The results of the association study were negative for comparisons between white and black alcoholics and controls, and no association was disclosed when either subtypes of alcoholics and different aspects of this condition were considered. These results, together with those available in the literature for other ethnic groups, suggest a minor role, if any, of the DRD4 gene in the susceptibility to alcoholism.

Lack of allelic association of dopamine D4 receptor gene polymorphisms with Parkinson's disease in a chinese population

Lack of allelic association of dopamine D4 receptor gene polymorphisms with Parkinson's disease in a chinese population

Lack of allelic association of dopamine D4 receptor gene polymorphisms with Parkinson's disease in a Chinese population.

Parkinson's disease (PD) is a neurodegenerative disease caused by a multitude of environmental, neurochemical, and genetic factors. The gene for human dopamine D4 receptor (DRD4) has been considered as a plausible candidate for the pathogenesis of PD. Different dopamine D4 receptor allelic forms have variable affinity toward certain neuroleptics such as clozapine, suggesting a role for dopamine D4 receptors in neurologic disorders. To test the hypothesis that the DRD4 polymorphism is associated with the susceptibility to Parkinson's disease, we have examined differences in allele frequencies of different DRD4 polymorphisms in 101 Chinese patients with PD and in 105 age-matched control subjects in Hong Kong. The DRD4 gene was analyzed by a non-radioactive polymerase chain reaction-based Southern hybridization with chemiluminescence detection. The number of polymorphic 48 base pair tandem repeats in exon 3 was identified in each study subject. The DRD4 alleles with high frequencies in the control subjects are 4-repeat allele (72.4%), 2-repeat allele (21.4%), and 7-repeat allele (3.8%) which accounted for over 97% of the total alleles in the elderly Chinese population. The most prevalent genotype in the control subjects is the 4/4 (47.6%), followed by 4/2 (38.6), 4/7 (7.6%), and 2/2 (3.0%). None of the variable number tandem repeat polymorphism showed evidence for genetic association with Parkinson's disease.

Brain event-related potentials, dopamine D2 receptor gene polymorphism, and smoking.

This paper explores the relationship between the DRD2 gene polymorphism, P300, and smoking. Both smoking and DRD2 have significant reducing effects on P300 amplitude. The effect of smoking is apparent only in the presence of the A1 allele of the DRD2 locus. Transmission/disequilibrium analyses show a negative association between the A2 allele and smoking initiation, suggesting a protective effect of this allele. When the sample is stratified into lower- and higher-P300 categories, we find a significant association between A1 and current smoking only in individuals with lower P300. Both concordance for smoking and DRD2 genotype are significant predictors of sib-pair similarity in P300 amplitude. These results suggest a synergistic effect of different neurogenetic risk factors contributing to nicotine dependence. Neurocognitive variation (P300) may moderate the association between DRD2 and smoking. Alternatively, DRD2 genotype may modulate the long-term impact of nicotine on neurocognitive functioning.

Dopamine D4 receptor gene polymorphisms and neuroleptic response in schizophrenia

Background: Dopamine D4 receptor (DRD4) gene polymorphisms are associated with various pharmacologic activities. This study investigated whether polymorphisms of 48-bp tandem repeats in the exon 3 of the DRD4 gene are related to neuroleptic response. Methods: The neuroleptic response at the acute stage of schizophrenia was assessed in 80 (48 men, 32 women) schizophrenic patients. The negative symptoms at remission were also rated. DRD4 genotype was established using the polymerase chain reaction. Patients with genotypes containing an allele with only two repeats (2-2, 2-3, 2-4, 2-6) were assigned to group I ( n = 38). Those homozygous for four 48-bp repeats were assigned to group II ( n = 42). Results: Thirteen (34.2%) of the 38 group I subjects and 26 (61.9%) of the 42 group II subjects had good neuroleptic response during acute stage treatment (χ 2 = 6.12, df = 1, p < .02). In remission, the rates of negative symptoms of blunt affect, avolition, and global negative rating were higher in group I than in group II. This was more prominent in men than in women. Conclusions: The presence of homozygous four 48-bp repeats in both alleles in exon 3 of the DRD4 gene is associated with good neuroleptic response during acute treatment, and with a lower prevalence of negative symptoms at remission, especially in male schizophrenic patients.

Dopamine D4 receptor gene polymorphism in children with attention deficit hyperactivity disorder (ADHD) — A biological marker?

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