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PubMed1996

Confinement of PGL, an imprinted gene causing hereditary paragangliomas, to a 2-cM interval on 11q22-q23 and exclusion of DRD2 and NCAM as candidate genes.

Paragangliomas of the head and neck region, also known as glomus tumours, are mostly benign tumours of neuro-ectodermal origin. We mapped the familial form by linkage analysis in 6 families to chromosome region 11q22-q23, between the markers STMY and CD3D which currently span a 16-cM interval. Here, we performed detailed haplotype analysis of this region in a single Dutch multibranch 7-generation family. A region of 2 cM between the markers D11S938/D11S4122 and D11S1885 was shared between all patients of whom disease haplotypes could be reconstructed. In support of this localization, a recombination observed in a small French family with 2 affected nieces places the PGL gene proximal to marker D11S908, genetically coincident with D11S1885.

Chromosome Mapping↗
PubMed2003

D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes.

The D2 dopamine receptor (DRD2) has been one of the most extensively investigated gene in neuropsychiatric disorders. After the first association of the TaqI A DRD2 minor (A1) allele with severe alcoholism in 1990, a large number of international studies have followed. A meta-analysis of these studies of Caucasians showed a significantly higher DRD2 A1 allelic frequency and prevalence in alcoholics when compared to controls. Variants of the DRD2 gene have also been associated with other addictive disorders including cocaine, nicotine and opioid dependence and obesity. It is hypothesized that the DRD2 is a reinforcement or reward gene. The DRD2 gene has also been implicated in schizophrenia, posttraumatic stress disorder, movement disorders and migraine. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in brains of subjects who carry the DRD2 A1 allele. In addition, pleiotropic effects of DRD2 variants have been observed in neurophysiologic, neuropsychologic, stress response, personality and treatment outcome characteristics. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the treatment of these disorders.

Humans↗
PubMed1997

D2 dopamine receptor A1 allele in Alzheimer disease and aging.

BACKGROUND: The apolipoprotein E4 (APOE*4) allele is a major risk factor for the common forms of late-onset Alzheimer disease (AD), but does not account for all the genetic variation in late-onset AD; hence, other genetic markers must be examined. The D2 dopamine receptor (DRD2) A1 allele is associated with abnormal brain function and decreased DRD2s. These receptors are decreased in hippocampus and amygdala in AD, and allele frequencies may vary with age. OBJECTIVE: To study APOE and DRD2 genotypes in patients with AD and cognitively intact controls of varying ages. DESIGN: The DRD2 and APOE genotypes were examined in 832 unrelated white subjects, including 554 patients with AD (486 sporadic; 68 familial) and 278 controls. Logistic regressions tested A1 allele effects on disease status and age, and DRD2 linkage with AD was investigated in 60 families with late-onset AD. SETTING: University medical centers. SUBJECTS: Patients (mean +/- SD age, 74.6 +/- 8.1 years; range, 52-98 years) had probable AD, according to standard consensus diagnostic criteria; controls (mean +/- SD age, 69.2 +/- 8.6 years; range, 50-93 years) were cognitively intact. MAIN OUTCOME MEASURES: Disease status, age, and DRD2 linkage with AD. RESULTS: No association between the DRD2 and APOE alleles was found, and the presence of the A1 allele did not increase the risk for AD. There was also no evidence of linkage between DRD2 and AD. Age analyses, including both patients and controls, indicated a decrease in A1 allele frequency with age. CONCLUSIONS: The A1 allele does not contribute to AD risk, alone or in combination with the APOE*4 allele. The DRD2 A1 allele frequencies decrease with age in both patients and controls. Thus, studies of DRD2 disease association need to control for age.

Aged↗
PubMed2004

Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence.

BACKGROUND: The role of the dopamine D2 receptor (DRD2) gene in the development of alcohol abuse or dependence is controversial. The controversy is due in part to the disparate definitions pertaining to the control groups used and to the definitions of subtypes in alcohol dependence. In the Han Chinese population, the alcohol dehydrogenase 1B*2/*2 (ADH1B*2/*2) genotype and the aldehyde dehydrogenase 2*2 (ALDH2*2) allele have been considered as protective factors against alcohol abuse or dependence. Moreover, the ADH1B and ALDH2 genes might be involved in dopamine metabolism. We hypothesized that the ADH1B and ALDH2 genes might interact with the DRD2 gene and that the association between the DRD2 gene and alcohol dependence might be affected by different ADH1B and ALDH2 genotypes. This study examined whether the DRD2 gene is associated with specific subtypes of alcohol dependence and evaluated the relationship between the DRD2 gene and alcohol-metabolizing genes in a specific subtype of alcohol dependence. METHODS: Of the 465 Han Chinese subjects who were recruited for the study, 71 were classified with pure alcohol dependence, 113 with both alcohol dependence and anxiety-depression (ANX/DEP ALC), and 129 with anxiety-depression but without alcohol dependence (ANX/DEP). The remaining 152 subjects were supernormal controls. All subjects were interviewed with the Chinese version of the modified Schedule of Affective Disorders and Schizophrenia-Lifetime; all alcohol dependence, anxiety, and major depressive diagnoses were made according to DSM-IV criteria. RESULTS: The DRD2 gene was not found to be associated with pure alcohol dependence or ANX/DEP, but was found to be associated with ANX/DEP ALC. Furthermore, the association between the DRD2 gene and ANX/DEP ALC was shown to be under the control of the ALDH2*1/*1 and ADH1B*1/*2 genotypes. CONCLUSIONS: ANX/DEP ALC is a specific subtype of alcohol dependence. Because ANX/DEP ALC was associated with the DRD2 gene only under the stratification of ADH1B*1/*2 or ALDH2*1/*1, the DRD2 gene might interact with the ADH1B gene and the ALDH2 gene, respectively, in the development of ANX/DEP ALC in the Taiwan Han Chinese population.

Adult↗
PubMed2005

Dopamine receptor D2 gene polymorphisms are associated in Taiwanese children with Tourette syndrome.

The pathophysiology of Tourette syndrome may involve the dopamine system. Dysfunction of the dopamine receptor D2 gene leads to many neuropsychiatric disorders. The objective of this study is to test the hypothesis that the dopamine receptor D2 gene may play a role in Tourette syndrome. A total of 151 children with Tourette syndrome and 183 normal control subjects were included in the study. Polymerase chain reaction was used to identify the Taq I DRD2 and DRD2 (H313H) polymorphisms of the dopamine receptor D2 gene. The genotype proportions of Taq I DRD2 and DRD2 (H313H) polymorphisms in the two groups were significantly different (P < 0.01 for both). The odds ratio for developing Tourette syndrome in individuals with the Taq I DRD2 A1 homozygote was 2.253 (95% confidence interval, 1.124-4.517) compared with individuals with the Taq I DRD2 A2 homozygote. The odds ratio for developing Tourette syndrome in individuals with the DRD2 (H313H) C homozygote was 2.96 (95% confidence interval, 1.398-6.269) compared with individuals with DRD2 (H313H) T homozygote. This study has demonstrated an association between the dopamine receptor D2 gene and Tourette syndrome. These data suggest that the dopamine receptor D2 gene or a closely linked gene might be one of the susceptibility factors for Tourette syndrome.

Asian People↗
PubMed1998

The D2 dopamine receptor gene: a review of association studies in alcoholism and phenotypes.

The role of the D2 dopamine receptor (DRD2) gene in alcoholism and other substance use disorders has come under intense investigation since the minor TaqI A (A1) allele of the DRD2 gene was first reported to be associated with alcoholism. In a meta-analysis of 15 US and international studies of European (non-Hispanic) Caucasians, consisting of 1015 alcoholics (more severe and less severe) and 898 controls (unassessed and assessed for alcoholism), alcoholics had a higher prevalence (p < 10(-7)) and frequency (p < 10(-5)) of the A1 allele than controls. The prevalence of the A1 allele was 1.5-fold higher in more severe than less severe alcoholics (p < 10(-4)), whereas unassessed controls had a twofold higher prevalence of the A1 allele than assessed controls (p < 10(-4)). Whereas more severe alcoholics had a threefold higher A1 allelic prevalence than assessed controls (p < 10(-10)), A1 allelic prevalence was virtually identical in less severe alcoholics and in unassessed controls. The A1 allele has also been associated with other drug problems including cocaine, nicotine, and polysubstance abuse. Furthermore, the minor TaqI B (B1) allele of the DRD2 gene has been associated with alcoholism and psychostimulant (cocaine, amphetamine) abuse. Beyond association studies, phenotypic differences exist between genotypes containing the TaqI A minor (A1A1 and A1A2) and major (A2A2) alleles of the DRD2. These different phenotypes have been identified through a number of approaches, including pharmacological, neurophysiological, neuropsychological, stress, personality, metabolic, and treatment studies. In conclusion, the present review suggests that the type of alcoholics and the nature of controls used are among critical factors in DRD2 association studies in alcoholism. Intronic mutations in both the 3'(TaqI A) and 5'(TaqI B) regions of the DRD2 associate with alcoholism and other drug use disorders. The identification of phenotypes of DRD2 genotypes suggests that the observed intronic DRD2 mutations may have functional consequences that predispose individuals to a variety of substance use disorders.

Alcoholism↗
PubMed1999

Dopamine D2 receptor gene not associated with symptomatology of mood disorders.

Dopamine D2 receptor gene (DRD2) variants have been implicated in the pathogenesis of psychiatric disorders. Many studies have, however, failed to replicate the original association of DRD2 with schizophrenia and mood disorders. A possible reason for this may lie in the definition of phenotype, which is traditionally based on psychiatric diagnosis. In this study we investigated the possibility that variants of the DRD2 gene might be associated with symptomatology in a sample of mood disorder subjects. Forty-seven inpatients affected by bipolar disorder (Diagnostic and Statistical Manual of Mental Disorders IV) were assessed at admission by the Operational Criteria for Psychotic Illness and were typed for DRD2 variants using polymerase chain reaction techniques. DRD2 was not associated with excitement, depression, delusion, and disorganization symptoms. Gender did not influence results significantly. Among early onset subjects DRD2*1 was associated with disorganized symptoms. In our sample DRD2 variants did not markedly influence psychopathology among mood disorder subjects. We observed a trend toward higher disorganization among DRD2*1 subjects.

Adult↗
PubMed2002

[Study on the association between smoking behavior and dopamine receptor D2 gene polymorphisms among lung cancer cases].

OBJECTIVE: To investigate the possible association between dopamine D2 receptor (DRD2) TaqI A and TaqI B genotypes as well as smoking behavior and the risk of lung cancer among Chinese Han people. METHODS: PCR was used to perform genotyping on peripheral WBC DNA from 326 lung cancer patients and 326 age, sex and ethnicity-matched healthy controls. Subjects were interviewed to obtain relevant information and lifetime history of tobacco use. RESULTS: There were no statistically significant differences in the distribution of DRD2 genotypes between lung cancer cases and controls. The DRD2 genotypes and smoking status showed no correlation among cases and among controls as well. However, among controls, the frequency of the DRD2 * A2/A2 genotype in smokers who smoked > or = 25 cigarettes/day appeared to be higher than that in those who smoked < 25 cigarettes/day (42.5% versus 26.1%, P = 0.047). A similar trend was also found for the DRD2 * B2/B2 genotype, which was linked to the DRD2 * A2/A2 genotype, although the difference was not significant (40.0% versus 26.1%, P = 0.091). In contrast to controls, no association was found between the DRD2 genotypes and smoking among lung cancer cases. CONCLUSION: Our results suggested that DRD2 * A2/A2 genotype might be associated with a greater smoking intensity in Chinese. Further studies are needed to confirm this preliminary finding.

Aged↗
PubMed2004

Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy.

We decided to test the hypothesis that possibly by combining a narcotic antagonist and amino-acid therapy consisting of an enkephalinase inhibitor (D-phenylalanine) and neurotransmitter precursors (L-amino- acids) to promote neuronal dopamine release might enhance compliance in methadone patients rapidly detoxified with the narcotic antagonist Trexan (Dupont, Delaware). In this regard, Thanos et al. [J. Neurochem. 78 (2001) 1094] and associates found increases in the dopamine D2 receptors (DRD2) via adenoviral vector delivery of the DRD2 gene into the nucleus accumbens, significantly reduced both ethanol preference (43%) and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. This DRD2 overexpression similarly produced significant reductions in ethanol non-preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This work further suggests that high levels of DRD2 may be protective against alcohol abuse [JAMA 263 (1990) 2055; Arch, Gen. Psychiatr. 48 (1991) 648]. The DRD2 A1 allele has also been shown to associate with heroin addicts in a number of studies. In addition, other dopaminergic receptor gene polymorphisms have also associated with opioid dependence. For example, Kotler et al. [Mol. Phychiatr. 3 (1997) 251] showed that the 7 repeat allele of the DRD4 receptor is significantly overpresented in the opioid-dependent cohort and confers a relative risk of 2.46. This has been confirmed by Li et al. [Mol. Psychiatry 2 (1997) 413] for both the 5 and 7 repeat alleles in Han Chinese case control sample of heroin addicts. Similarly Duaux et al. [Mol. Psychiatry 3 (1998) 333] in French Heroin addicts, found a significant association with homozygotes alleles of the DRD3-Bal 1. A study from NIAAA, provided evidence which strongly suggests that DRD2 is a susceptibility gene for substance abusers across multiple populations (2003). Moreover, there are a number of studies utilizing amino-acid and enkephalinase inhibition therapy showing reduction of alcohol, opiate, cocaine and sugar craving behavior in human trials (see Table 1). Over the last decade, a new rapid method to detoxify either methadone or heroin addicts utilizing Trexan sparked interest in many treatment centers throughout the United States, Canada, as well as many countries on a worldwide basis. In using the combination of Trexan and amino-acids, results were dramatic in terms of significantly enhancing compliance to continue taking Trexan. The average number of days of compliance calculated on 1000 patients, without amino-acid therapy, using this rapid detoxification method is only 37 days. In contrast, the 12 subjects tested, receiving both the Trexan and amino-acid therapy was relapse-free or reported taking the combination for an average of 262 days (p < 0.0001F). Thus coupling amino-acid therapy and enkephalinase inhibition while blocking the delta-receptors with a pure narcotic antagonist may be quite promising as a novel method to induce rapid detox in chronic methadone patients. This may also have important ramifications in the treatment of both opiate and alcohol-dependent individuals, especially as a relapse prevention tool. It may also be interesting too further test this hypothesis with the sublingual combination of the partial opiate mu receptor agonist buprenorphrine.

Adult↗