Alcoholism and the D<sub>2</sub> Receptor Gene

Cook, Brian L.; Wang, Zhe Wu; Crowe, Raymond R.; Hauser, Richard L.; Freimer, Martin

doi:10.1111/j.1530-0277.1992.tb00683.x

Cited by 89 publications

(45 citation statements)

References 24 publications

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“…This association has been supported in several, [2][3][4][5] but not all subsequent studies. [10][11][12][13] The A1 allele was also found to be associated with prolonged P300 latency, reduced visuospatial preference, and low cerebral glucose utilization, all putative markers of alcoholism and dopamine function deficiency. [15][16][17] In addition, the A1 allele has also been associated with substance abuse, [6][7][8][9] which led to its conceptualization as a 'reward gene'.…”

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confidence: 99%

D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene

1998

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Alcoholism and substance abuse have been associated with a polymorphism in a noncoding region of the D 2 receptor gene (the A1 allele of the Taq1 'A' system) in several, [1][2][3][4][5][6][7][8][9] but not all 10-13 studies. In addition, the presence of the A1 allele has been associated with lower density of D 2 receptors in the caudate nucleus in one postmortem study. 14 If the Taq1 'A1' allele is in linkage disequilibrium with a mutation that decreases the expression of the D 2 receptor gene, it is conceivable that subjects with the A1 allele might be predisposed to behaviors which stimulate dopamine transmission, such as alcoholism or substance abuse. In this study, we attempted to confirm the association between the A1 allele and lower D 2 receptor density, and explored a possible association between the B1 allele and D 2 receptor expression. Genotypes at the Taq1 'A' and 'B' systems were determined in 70 subjects who underwent in vivo measurement of D 2 receptors-binding potential with single photon emission computerized tomography (SPECT) and the selective dopamine D 2 receptor radiotracer [ 123 I]IBZM. [ 123 I]IBZM-binding potential was identical in A1 carriers (ie, subjects heterozygous or homozygous for that allele) (230 ± 85 ml g −1 , n = 27) and A1 noncarriers (231 ± 70 ml g −1 , n = 43). Similarly, we found no effect of the B1 allele on [ 123 I]IBZM-binding potential. In conclusion, the results of this study failed to replicate the previously reported association between A1 allele and lower D 2 receptor expression.In 1990, Blum et al 1 reported an association between alcoholism and a polymorphism in a noncoding region of the D 2 receptor gene (the A1 allele of the Taq1 'A' system). This association has been supported in several, 2-5 but not all subsequent studies. 10-13 The A1 allele was also found to be associated with prolonged P300 latency, reduced visuospatial preference, and low cerebral glucose utilization, all putative markers of alcoholism and dopamine function deficiency. [15][16][17] In addition, the A1 allele has also been associated with substance abuse, 6-9 which led to its conceptualization as a 'reward gene'. Together, these data suggest that this polymorphism might affect dopamine transmission in a way that predisposes subjects to 'reward seeking' behavior, i.e. behaviors aiming at increasing stimulation of dopamine transmission.The mechanism underlying the association between the A1 allele and vulnerability to addictive behaviors is unclear, since the Taq1 'A' polymorphism is not located in the coding region of the gene and a direct effect of this polymorphism on the structure of the D 2 receptor gene has been excluded by denaturing gradient gel electrophoresis mutational analysis study. 18 Noble et al 14 described an association between the A1 allele and decreased D 2 receptor density expressed in postmortem striatal samples from alcoholic and nonalcoholic subjects. If replicated, this observation might suggest that this polymorphism is in linkage disequilibrium with an unknown muta...

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D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene

1998

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“…After Blum et al [1990] reported that the frequency of TaqI A1 allele of DRD2 was higher in alcoholics than in nonalcoholic controls, several subsequent studies of other populations have replicated the finding Comings et al, 1991;Noble et al, 1991;Parsian et al, 1991;Amadeo et al, 1993;Neiswanger et al, 1995a]. However, many failed to do so [Bolos et al, 1990;Gelernter et al, 1991;Cook et al, 1992;Goldman et al, 1992;Turner et al, 1992;Arinami et al, 1993;Suarez et al, 1994;Sander et al, 1995;Lu et al, 1996].…”

Section: Introductionmentioning

confidence: 99%

“…Since there is a wide variation in the allelic frequency of TaqI A1 of DRD2 among different populations [Barr and Kidd, 1993], one possibility is confounding by population admixture due to unmatched ethnicity between cases and controls [Gelernter et al, 1993;Pato et al, 1993]. The sample size of previous studies, such as Cook et al [1992] and Lu et al [1996], may not have sufficient power to detect the association. Some researchers have suggested that the association may exist exclusively among severe alcoholics Parsian et al, 1991;Arinami et al, 1993], and the prevalence of DRD2 A1 allele has been found to be higher in more severe alcoholics than in less severe ones Noble et al, 1994].…”

Section: Introductionmentioning

confidence: 99%

Dopamine D2 receptor gene and alcoholism among four aboriginal groups and Han in Taiwan

Chen

Hsu

et al. 1997

Am. J. Med. Genet.

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Previous studies examining the putative association between DRD2 TaqI A1 and alcoholism have produced conflicting results. Major critiques of such studies include potential confounding arising from population admixture by inappropriate selection of controls, failure to screen out substance abusers from controls, and the failure to assess the severity of alcoholics. To address these issues, we compared the allelic frequency of two polymorphisms of DRD2, TaqI A and NcoI, among severe alcoholics and their ethnically matched nonalcoholic controls within four major aboriginal groups and Han (Chinese) in Taiwan. The sample of alcoholics and controls examined for the five groups included 36 and 31 (Atayal), 24 and 23 (Ami), 58 and 58 (Bunun), 35 and 35 (Paiwan), and 50 and 66 (Han). A borderline association between TaqI A1 and alcoholism among the Ami (P = 0.08) and an association between NcoI N1 and alcoholism among Han (P = 0.01) were found. Results of haplotype analysis further confirm that the frequency of haplotype A1N1 was higher in alcoholics than in controls for the Ami (P = 0.01) and Han (P = 0.03). If controls with tobacco abuse were excluded from the analysis, the results remained unchanged. Severity in medical complications of alcohol dependence with withdrawal symptoms was not associated with higher prevalence of DRD2 TaqI A1 or NcoI N1 alleles. The absence of an association between DRD2 and alcoholism among the three aboriginal groups suggests either a higher rate of phenocopies among aboriginal alcoholics or genetic heterogeneity in the susceptibility to alcoholism.

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“…Several case/control studies have investigated allelic variation in the TaqI A polymorphism but with controversial results. Several negative results were reported in comparisons of alcohol dependent and control individuals [Bolos et al, 1990;Gelernter et al, 1991;Cook et al, 1992;Turner et al, 1992;Arinami et al, 1993;Suarez et al, 1994] though many studies did obtain positive results for alcohol dependent individuals [Amadeo et al, 1993;Noble et al, 1994;Neiswanger et al, 1995] and for polysubstance abusers Lawford et al, 1997]. Averaging of A1 frequencies across 21 studies that included alcoholics and controls revealed greater frequency among alcoholics [Noble, 2003].…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

Hill

Hoffman

Zezza

et al. 2008

American J of Med Genetics Pt B

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Animal and human studies of addiction indicate that the D2 dopamine receptor (DRD2) plays a critical role in the mechanism of drug reward. D2 receptor density in the brains of alcoholics has been shown to be reduced relative to controls. Previous studies of DRD2 in association with alcohol dependence using variation in the TaqI A locus were highly controversial. Recently, a synonymous mutation, C957T, in the coding region of the human DRD2 gene has been identified which appears to have functional effects including alteration in receptor availability. In order to determine if susceptibility to alcohol dependence (AD) within multiplex alcohol dependence families would be altered by the C957T in the coding region of the D2 gene, within-family association was studied in members of Caucasian multiplex alcohol dependence families. Members of control families with no personal alcohol or substance dependence history were included for case/control comparisons. Analyses performed to detect within-family association showed evidence favoring an association for the C957T polymorphism (P = 0.038). Linkage analyses of polymorphisms in this region showed that only the C957T locus remained of interest (P = 0.015). Evidence for the C957T T allele having a role in AD susceptibility at the population level using a case/control comparison was statistically marginal (P = 0.062), but was consistent with the family data results. These results support a role for DRD2 as a susceptibility gene for alcohol dependence within multiplex families at high risk for developing alcohol dependence.

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Alcoholism and the D₂ Receptor Gene

Cited by 89 publications

References 24 publications

D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene

D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene

Dopamine D2 receptor gene and alcoholism among four aboriginal groups and Han in Taiwan

Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

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Alcoholism and the D2 Receptor Gene

Cited by 89 publications

References 24 publications

D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene

D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene

Dopamine D2 receptor gene and alcoholism among four aboriginal groups and Han in Taiwan

Dopaminergic mutations: Within‐family association and linkage in multiplex alcohol dependence families

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Alcoholism and the D₂ Receptor Gene