Association of the dopamine D2 receptor gene with alcohol dependence: haplotypes and subgroups of alcoholics as key factors for understanding receptor function

Objectives The dopamine D2 receptor (DRD2) plays an important role in the reinforcing and motivating effects of ethanol. Several polymorphisms have been reported to affect receptor expression. The amount of DRD2, expressed in a given individual, is the result of the expression of both alleles, each representing a distinct haplotype. We examined the hypothesis that haplotypes composed of polymorphisms, associated with reduced receptor expression, are more frequent in alcoholics compared with healthy individuals. Methods The polymorphisms - 141 ins/del, C957T, A1385G, and TaqIA were genotyped in a case-control sample comprising 360 alcoholics and 368 controls, and in a family-based sample of 65 trios. To investigate more homogenous groups, we constructed two subgroups with respect to age at onset and antisocial personality disorder. In addition, a subgroup with positive family history of alcoholism was investigated. Results The haplotypes I-C-G-A2 and I-C-A-All occurred with a higher frequency in alcoholics [P=0.026, odds ratio (OR): 1.340; P=0.010, OR: 1.521, respectively]. The rare haplotype I-C-A-A2 occurred less often in alcoholics (P=0.010, OR: 0.507), and was also less often transmitted from parents to their affected offspring (11 vs. 7). Among the subgroups, I-C-G-A2 and I-C-A-All had a higher frequency in Cloninger 1 alcoholics (P=0.083 and 0.001, OR: 1.917, respectively) and in alcoholics with a positive family history (P=0.031, OR: 1.478; P=0.073, respectively). Cloninger 2 alcoholics had a higher frequency of the rare haplotype D-T-A-A2 (P<0.001, OR: 4.614) always compared with controls. In patients with positive family history haplotype I-C-A-A2 (P=0.004, OR: 0.209), and in Cloninger 1 alcoholics haplotype I-T-A-All (P=0.045, OR: 0.460) were less often present. Conclusion We confirmed the hypothesis that haplotypes, which are supposed to induce a low DRD2 expression, are associated with alcohol dependence. Furthermore, supposedly high-expressing haplotype weakened or neutralized the action of low-expressing haplotypes. Pharmacogenetics and Genomics 19:513-527 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.