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.