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PubMed1991

Direct sequencing of the dopamine D2 receptor (DRD2) in schizophrenics reveals three polymorphisms but no structural change in the receptor.

The dopamine D2 receptor gene (gene symbol DRD2) is a candidate gene for schizophrenia because the potency of certain neuroleptics correlates with their affinity for this receptor. Seven regions of likely functional significance including the coding sequences and the splice junctions were fully sequenced in the dopamine D2 receptor of 14 schizophrenics (and partially in several others) meeting DSM-III-R diagnostic criteria and in four unaffected non-Caucasians (97 kb of total sequence). No structural changes were found, suggesting that alteration in the structure of the dopamine D2 receptor is not commonly involved in the etiology of schizophrenia. However, two common and one uncommon intragenic polymorphisms were found. At least one of the polymorphisms was informative for linkage in 70% of Caucasians and 78% of Koreans.

Base Sequence↗
PubMed2007

Heavy nicotine and alcohol use in alcohol dependence is associated with D2 dopamine receptor (DRD2) polymorphism.

Cigarette smoking in those who are alcohol dependent is associated with higher morbidity and mortality. The A1 allele of the D2 dopamine receptor (DRD2) gene has been independently associated with alcohol and nicotine dependence. Whether this polymorphism is associated with nicotine dependence in those who are also alcohol dependent has not been investigated. Subjects were 84 (61 males; 23 females) Caucasian DSM IV diagnosed nicotine- and alcohol-dependent subjects sampled from consecutive admissions to a hospital alcohol detoxification ward. Data were obtained through standardised measures of nicotine and alcohol consumption and dependence severity. A1+ allelic (A1/A1 or A1/A2 genotype) compared to A1- allelic (A2/A2 genotype only) patients were characterised by higher levels of alcohol and cigarette consumption. A1+ allelic patients reported greater alcohol dependence severity, but not nicotine dependence severity. When the combined nicotine and alcohol dose was examined, A1+ allelic patients consumed significantly more of these drugs than their A1- allelic counterparts.

Adult↗
PubMed2003

The A1 allele of the DRD2 gene (TaqI A polymorphisms) is associated with antisocial personality in a sample of alcohol-dependent patients.

BACKGROUND: Presence of A1 allele of the DRD2 gene has been associated with a predisposition for alcoholism although there are limited data about its phenotypic expression in alcoholism. OBJECTIVES: To determine the importance of the A1 allele in clinical variables of alcohol dependence. METHODOLOGY: A sample of 103 alcohol-dependent males was studied. All patients were recruited consecutively from the general hospital and community settings. The diagnostics were made with the structured clinical interview for DSM-III-R (SCID); and the International Personality Disorder Examination (IPDE). Diagnosis of family alcoholism was made by direct interview or with the Research Diagnostic Criteria-Family History (RDC-FH). The Addiction Severity Index (ASI) and the Severity of Alcohol Dependence Scale (SADS) were used to assess alcohol dependence severity. Genotyping was done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. RESULTS: Approximately 39% of the sample carried the A1 allele (A1+ group). This group had higher prevalences of antisocial personality disorder (60% vs. 15.9%); and alcoholism family history (72.5% vs. 52.4%). Also A1+ had early onset alcohol abuse and more drinking problems. The presence of A1+ was the main factor to explain the diagnosis of antisocial personality disorder, but the weight of this factor was not sufficient to explain the complications assessed by the ASI. CONCLUSIONS: Our results support the existence of an association between the A1 allele and factors resulting from dopaminergic deficiency, otherwise denominated reward deficiency syndrome.

Adult↗
PubMed2005

The TaqIA polymorphism linked to the DRD2 gene is related to lower attention and less inhibitory control in alcoholic patients.

The TaqIA polymorphism linked to the DRD2 gene has been associated with alcoholism. The aim of this work is to study attention and inhibitory control as per the continuous performance test and the stop task in a sample of 50 Spanish male alcoholic patients split into two groups according to the presence of the TaqIA1 allele in their genotype. Our results show that alcoholics carrying the TaqIA1 allele present lower sustained attention and less inhibitory control than those patients without such allele.

Adult↗
PubMed2005

Association of DRD2 gene variant with schizophrenia.

Schizophrenia is a complex multifactorial disorder for which the pathobiology still remains elusive. Dysfunction of the dopamine D2 receptor signaling has been associated with the illness, but numerous studies provide confounding results. This study investigates the association of synonymous polymorphisms (His313 and Pro319) in the dopamine D2 receptor gene with schizophrenia using a case-control approach, with 101 cases and 145 controls. Our results demonstrated that genotype distribution for the His313 polymorphism was significantly different between schizophrenia patients and control subjects (p=0.0012), while the Pro319 polymorphism did not show any association with the disease. The results suggest that the synonymous SNP His313 in DRD2 may be associated with the illness. However, there is a need for further replication studies with larger sample sets.

Adolescent↗
PubMed1997

No association of the Ser/Cys311 DRD2 molecular variant with schizophrenia using a classical case control study and the haplotype relative risk.

Arinami et al. (1994) reported an association between the Ser311/Cys311 variant of the DRD2 gene and schizophrenia in a Japanese population. We did not find statistically significant differences in the distribution of the allele frequencies between schizophrenics (103) and controls (97) in a case-control sample (chi 2 = 2.07; p = 0.150) or in 64 nuclear families with the haplotype relative risk (HRR) design (chi 2 = 0.13; p = 0.718). Our results seem to exclude a main involvement of this variant of the dopamine D2 receptor gene in the etiopathogenesis of schizophrenia.

Age of Onset↗
PubMed2000

Reappraisal of the association between the DRD2 gene, alcoholism and addiction.

We analysed the impact of the TaqI A1 allele of the D2 dopamine receptor gene on the risk for alcoholism, trying to depict three explanations frequently proposed to explain discrepancies in association and linkage studies: that the A1 allele may act as a marker rather than as a vulnerability factor, that stratification biases and unevaluated controls may explain positive results, and that the A1 allele is modifying the phenotype rather than increasing the risk for alcoholism. We thus tested another (dinucleotide STRP) marker within the DRD2 gene, selected a new homogenous sample of 113 alcoholic patients and 49 unaffected controls strictly matched for ethnic origins, and systematically assessed both samples with a semi-structured interview to detect (in both samples) alcohol dependence, but also such related traits as specificities of complications. The frequency of the A1 allele was not significantly different between alcoholics and controls but when comparing different subgroups of alcoholics, the A1 allele was significantly more frequent in alcoholic patients with somatic complications (OR = 3.00, CI[1.37-6.62]), social and professional complications (OR = 2. 72, CI[1.25-5.90]), or with co-morbid dependence (OR = 2.88, 95% IC [1.16-7.15]). The association for co-morbid dependence and somatic complications was also positive when taking into consideration both STRP and TaqIA polymorphisms. The A1 allele does not increase the risk for alcoholism per se in our sample, but may be involved in a related trait which is partially dependent on the diagnosis of alcoholism, through a disequilibrium with another close mutation.

Adult↗
PubMed1999

Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5.

The dopaminergic system has been implicated in the aetiology of mood disorders. We conducted family-based association studies for polymorphisms at three genes involved in the metabolism of dopamine: dopamine transporter (DAT1), dopamine-beta-hydroxylase (DBH) and catechol-O-methyl transferase (COMT); and three dopamine receptors: DRD2, DRD3 and DRD5. We used a sample of 122 parent-offspring trios of British Caucasian origin where the proband had bipolar disorder I (BPI), and analysed the results with the transmission/disequilibrium test (TDT) which is robust to hidden population stratification. No statistically significant differences were found between transmitted and not transmitted alleles for any of the polymorphisms studied.

Adult↗
PubMed2005

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps <0.05 and 0.01, respectively). Consistent with the separate biological pathways involved (receptor, transporter), carriers of both polymorphisms had markedly higher craving responses compared to those with neither (P<0.0006), reflecting additive effects. Findings provide support for the role of dopamine in cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Adult↗
PubMed2004

Stress-induced cigarette craving: effects of the DRD2 TaqI RFLP and SLC6A3 VNTR polymorphisms.

Animal models have long implicated dopamine in stress-induced craving for a variety of addictive substances. However, translational studies of dopamine, stress and craving in humans are lacking. Based on the animal literature, this study's objective was to test the hypothesis that cigarette smokers carrying specific variants in dopamine-related genes would have heightened levels of cigarette craving following exposure to a laboratory stressor. Cigarette craving induced by controlled exposure to a laboratory stressor was assessed in healthy adult smokers (n=108) recruited by advertisement. Significantly stronger stress-induced cigarette craving was found for individuals carrying either the DRD2 (D2 dopamine receptor gene) A1, or the SLC6A3 (dopamine transporter gene) nine-repeat allelic variants. Stress-induced craving was markedly higher for those carrying both alleles, compared to those with neither, consistent with the separate biological pathways involved (receptor, transporter). Findings provide strong support for the possibility that dopamine involvement in stress-induced craving well established in animal models also applies to humans, and suggest a potential genetic risk factor for persistent smoking behavior.

Adult↗
PubMed2001

Polymorphisms at the DRD2 locus in early-onset alcohol dependence in the Indian population.

The susceptibility to alcohol dependence is probably of polygenic origin. Association studies have attempted to identify possible candidate genes that may contribute to the risk to developing dependence. Severe forms of the alcoholism phenotype have been associated with an increased frequency of the Taq A1 allele at the DRD2 locus. Ethnic stratification and non-comparable phenotype may have contributed to the contradictory results in previous studies. We identified probands, using the Schedules of Assessment of Neuropsychiatry (SCAN) schedule, who had onset of alcohol dependence (ICD-10) before 25 years of age. Family members were interviewed using the Family Interview for Genetic Studies (FIGS) schedule to identify patients who had two first-degree relatives with alcohol dependence. Fifty subjects who fulfilled the criteria were selected for the study. These were compared to a normal population from a similar background. The allele frequencies did not differ between the two groups. The Taq1a polymorphism does not seem to be associated with alcoholism in this group of severely affected, young age of onset probands in the southern Indian population.

Journal Article↗
PubMed1993

DRD2 dopamine receptor genotype, linkage disequilibrium, and alcoholism in American Indians and other populations.

We defined interpopulation differences in the frequency of the dopamine D2 receptor DRD2/Taq1 A1 allele, which has previously been associated with alcoholism. Frequencies of the A1 allele in unrelated subjects were 0.18 to 0.20 (se = 0.02 to 0.03) in several Caucasian populations previously assessed, 0.38 (+/- 0.05) in American Blacks (n = 44), 0.63 (+/- 0.07) in Jemez Pueblo Indians (n = 23), and 0.80 (+/- 0.04) in Cheyenne Indians (n = 52). The existence of large interpopulation differences in the frequency of the Taq1 alleles suggests that associations to disease status could readily be generated or masked if disease and control groups were uneven in ethnic composition. To address the possibility that the 4-fold higher frequency of the A1 allele in Cheyenne Indians was related to an increased vulnerability to alcoholism in that population, 47 Cheyenne Indians were psychiatrically interviewed and blind-rated. However, there was no significant difference between interviewed controls (0.73 +/- 0.06, n = 24), subjects with alcoholism and/or drug abuse (0.74 +/- 0.06, n = 23) and noninterviewed population controls (0.87 +/- 0.05, n = 20). Legitimate association of the DRD2/Taq1 allele to alcoholism would presumably require it to be in linkage disequilibrium (nonrandom association) with a functional mutation at DRD2 or elsewhere. The level of disequilibrium would vary between populations and could place an upper bound on the strength of an association.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Increased cerebral activity in Parkinson's disease patients carrying the DRD2 TaqIA A1 allele during a demanding motor task: a compensatory mechanism?

Previous studies suggest that neuroimaging techniques are useful for detecting the effects of functional genetic polymorphisms on brain function in healthy subjects or in patients presenting with psychiatric or neurodegenerative conditions. Former evidence showed that individuals carrying risk alleles displayed broader patterns of brain activity during behavioural and cognitive tasks, despite being clinically comparable to non-carriers. This suggests the presence of compensatory brain mechanisms. In the present study, we investigated this effect in Parkinson's disease (PD) patients carrying the DRD2 TaqIA A1 allelic variant. This variant may confer an increased risk of developing the disease and/or influence the clinical presentation. During a complex sequential motor task, we evidenced by functional magnetic resonance imaging that A1 allele carriers activated a larger network of bilateral cerebral areas than non-carriers, including cerebellar and premotor regions. Both groups had similar clinical and demographic measures. In addition, their motor performance during the functional magnetic resonance experiment was comparable. Therefore, our conclusions, pending replication in a larger sample, seem to reflect the recruitment of compensatory cerebral resources during motor processing in PD patients carrying the A1 allele.

Adaptation, Physiological↗
PubMedDate not supplied

[Genetic association between the reduced amplitude of the P300 and the allele A1 of the gene which codifies the D2 dopamine receptor (DRD2) as possible biological markers for alcoholism].

INTRODUCTION: Over the last twenty years much work has been done to study the P300 in alcoholism. A systematically reduced amplitude, both in patients and in populations at risk (children of alcoholics) was found. Besides, studies on twins indicate that the waves of the evoked potentials are under genetic control. Furthermore, advances in molecular genetic techniques have clarified the part played by the allele A1 of the gene which codifies the D2 dopamine receptor in alcoholism. Only in recent years have studies been published relating them and in these they are considered to be risk markers for alcoholism. However, contradictory results have been obtained. DEVELOPMENT: The objective of this study is to review part of the literature and find evidence for and against the characteristics observed in the P300 and the possible part played by the DRD2 gene in the aetiology of alcoholism and the relationship between them. At the same time we consider the most relevant theoretical aspects of the role played by dopamine in the central nervous system, since some studies have shown that it is involved in the generation of P300 and reinforcement due to alcohol consumptions. Finally, we discuss the advantages and disadvantages that should be taken into account when considering the low amplitude of P300 and the presence of the A1 allele as diagnostic markers to identify populations at risk and thus avoid appearance of the disorder.

Alcoholism↗
PubMedDate not supplied

[Lack of association between 141C Ins/Del promoter polymorphism of DRD2 gene and schizophrenia].

Results of family studies show the importance of genetic factors in etiopathogenesis of schizophrenia. Susceptibility to the disease is probably due to an interaction of many genes. This association study was conducted to investigate frequencies of alleles and genotypes in a group of patients with schizophrenia and in healthy controls. We examined DRD2 gene promoter polymorphism--insertion or deletion of the cytosine in the position -141 of 5'-flanking region of this gene. No relationship between the polymorphism under study and schizophrenia has been found.

Adult↗
PubMed1996

Genetic variants of the human obesity (OB) gene: association with body mass index in young women, psychiatric symptoms, and interaction with the dopamine D2 receptor (DRD2) gene.

To examine the possible role of genetic variants of the OB gene in obesity we examined alleles of a dinucleotide repeat polymorphism, D7S1875, close to the gene, in a group of adult, non-Hispanic Caucasians. There was a significant correlation with body mass index (BMI) at age 26-30 years for males and females combined (P = 0.04) and females only (P = 0.028). Because of the frequent association between obesity and psychiatric symptoms all subjects were screened with the Symptom List 90 (SCL-90). There was a significant increase in scores for anxiety (P = 0.0005), depression (P = 0.003), and other behaviors for subjects homozygous for the OB1875 < 208-bp alleles. Analysis of covariance indicated that this was directly related to the OB alleles and not secondary to the presence of obesity. There was a significant association between the BMI at ages 16 to 40 and homozygosity for the OB1875 < 208-bp alleles and/or the presence of the DRD2 Taq A1 allele for males and females combined (P = 0.002 to 0.005), and for females alone (P = 0.0017 to 0.0005). For females alone these two genes accounted for up to 22.8% of the variance of the BMI. These results are consistent with the polygenic inheritance of obesity, the greater involvement of genetic factors in women and younger individuals, and suggest that variants of the OB gene are causally involved not only in human obesity but its associated behavioral disorders.

Adult↗
PubMed1996

DRD2, DRD3 and 5HT2A receptor genes polymorphisms in obsessive-compulsive disorder.

We performed an association analysis of the DRD2, DRD3 and 5HT2A genes polymorphisms in 67 Obsessive-Compulsive Disorder (OCD) patients and 54 healthy controls. There were no statistically significant differences in genotype or allele frequencies for any of the polymorphisms studied between OCD subjects and controls. For the subgrouped analysis, no results were significant after correction for multiple testing, although homozygosity of DRD2/A2A2 in subjects displaying vocal or motor tics approached significance compared to controls (Fisher exact test, P = 0.008). Our results may follow the notion that OCD patients with tics represent a different genetic subtype of the disease.

Adolescent↗