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.

Haplotypes at the DRD2 locus and severe alcoholism.

Association studies of the minor TaqI A allele of the D(2) dopamine receptor (DRD2) gene with alcoholism have produced conflicting findings. Failure to assess alcoholics for severity of their disorder and to screen controls for substance use have been proposed as causes for the discrepant results. In the present study, five diallelic sites spanning the DRD2 gene were determined in combined Caucasian (non-Hispanic) studies of more severe alcoholics (n = 92) and controls screened for substance use (n = 85). The frequency of the minor alleles at the 3'-untranslated site (TaqI A) and two intronic sites (TaqI B and intron 6) of the DRD2 gene were each strongly associated with alcoholism. Moreover, the alcoholics compared with the controls at these three sites had a significantly higher frequency of the minor/major allele heterozygote haplotype combination (A1/A2 B1/B2 T/G) than the major allele homozygote haplotype combination (A2/A2 B2/B2 G/G). However, exon 7 and promoter alleles were not associated with alcoholism. In neither the alcoholics nor in the controls were there departures from Hardy-Weinberg equilibrium at any of the five sites examined. The most significant diallelic composite genotypic disequilibria were found when comparisons were made between TaqI A and TaqI B, TaqI A and intron 6, and TaqI B and intron 6 sites. Weaker but still significant disequilibria were observed when TaqI A and exon 7, TaqI B and exon 7, intron 6 and exon 7, and promoter and exon 7 sites were compared. However, no significant disequilibria were noted when TaqI A and promoter, TaqI B and promoter, and intron 6 and promoter sites were compared. In sum, the study found significant evidence for association of the minor alleles in the untranslated sites of the DRD2 gene and their haplotypes with the more severe alcoholic phenotype.

D2 and D4 dopamine receptor polymorphisms and personality.

The relationship of various dimensions of temperament, measured by the Tridimensional Personality Questionnaire (TPQ), to polymorphisms of the D2 dopamine receptor (DRD2) and D4 dopamine receptor (DRD4) genes was determined in 119 healthy Caucasian boys who had not yet begun to consume alcohol and other drugs of abuse. Total Novelty Seeking score of the TPQ was significantly higher in boys having, in common, all three minor (A1, B1, and Intron 6 1) alleles of the DRD2 compared to boys without any of these alleles. Boys with the DRD4 7 repeat (7R) allele also had a significantly higher Novelty Seeking score than those without this allele. However, the greatest difference in Novelty Seeking score was found when boys having all three minor DRD2 alleles and the DRD4 7R allele were contrasted to those without any of these alleles. Neither the DRD2 nor the DRD4 polymorphisms differentiated total Harm Avoidance score. Whereas subjects having all three minor DRD2 alleles had a significantly higher Reward Dependence 2 (Persistence) score than subjects without any of these alleles, no significant difference in this personality score was found between subjects with and without the DRD4 7R allele. In conclusion, DRD2 and DRD4 polymorphisms individually associate with Novelty Seeking behavior. However, the combined DRD2 and DRD4 polymorphisms contribute more markedly to this behavior than when these two gene polymorphisms are individually considered.

D2 dopamine receptor polymorphism and brain regional glucose metabolism.

Positron emission tomography (PET) studies have shown decreased glucose metabolism in brain regions of detoxified alcoholics and cocaine abusers. However, it is not clear whether this decrease is due to chronic drug abuse or a pre-existing condition. Molecular genetic studies have found an association of the D2 dopamine receptor (DRD2) A1 allele with alcoholism and drug abuse. Moreover, reduced central dopaminergic function has been suggested in subjects who carry the A1 allele (A1+) compared with those who do not (A1-). In the present study, using 18F-deoxyglucose, regional glucose metabolism was determined in healthy nonalcohol/nondrug-abusing subjects with the A1+ or A1- allele. The mean relative glucose metabolic rate (GMR) was significantly lower in the A1+ than the A1- group in many brain regions, including the putamen, nucleus accumbens, frontal and temporal gyri and medial prefrontal, occipito-temporal and orbital cortices. Decreased relative GMR in the A1+ group was also found in Broca's area, anterior insula, hippocampus, and substantia nigra. A few brain areas, however, showed increased relative GMR in the A1+ group. Since polymorphism of the DRD2 gene is commonly observed in humans, the importance of differentiating A1+ and A1- alleles subjects in PET studies is suggested.

Association of the D2 dopamine receptor A1 allele with alcoholism: medical severity of alcoholism and type of controls.

D2 dopamine receptor (DRD2) A1 allele frequency was determined in alcoholics of varying medical severity from three different inpatient settings and in various controls. A1 frequency was .15 in 68 alcoholics in a detoxification unit (group A), .19 in 90 alcoholics in a rehabilitation unit (group B), and .31 in 43 alcoholics in a gastroenterology unit (group C). Group C had a higher A1 frequency than group B (p = .045) or group A (p = .005) alcoholics. In 46 controls (group D), A1 frequency was .18. In subsets of these controls, A1 frequency was .14 in 39 subjects with a negative family history (FH-) of alcoholism (group E), .06 in 34 subjects without previous hazardous alcohol consumption (group F), and .05 in 30 subjects with FH- and without previous hazardous alcohol consumption (group G). A1 frequency was significantly higher in group C alcoholics than group F (p = .0002) or group G (p = .0002) controls; however, no A1 frequency difference was found among group A alcoholics and any of the control groups. The severity of alcoholism and the type of controls used are important determinants of DRD2 A1 allele association with alcoholism.