title: Association of the dopamine D2 receptor gene with alcohol dependence: haplotypes and subgroups of alcoholics as key factors for understanding receptor function.
abstract: OBJECTIVE
  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 -141ins/del, C957T, A1385G, and TaqlA 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-A1 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 (1 vs.7). Among the subgroups, I-C-G-A2 and I-C-A-A1 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-A1 (P=0.045 OR: 0.460) were less often present.
  
  
  CONCLUSIONS
  We confirmed the hypothesis that haplotypes, which are supposed to induce a low DRD2 expression, are associated with alcohol dependence. Furthermore, supposedly high-expressing haplotypes weakened or neutralized the action of low-expressing haplotypes.
authors: Charité - Universitätsmedizin Berlin, Klinik für Psychiatrie and Psychotherapie, Campus Benjamin Franklin, Berlin, Germany.
authors: Adrian
authors: A
authors: Kraschewski
authors: Jörn
authors: J
authors: Reese
authors: Ion
authors: I
authors: Anghelescu
authors: Georg
authors: G
authors: Winterer
authors: Lutz G
authors: LG
authors: Schmidt
authors: Jürgen
authors: J
authors: Gallinat
authors: Ulrich
authors: U
authors: Finckh
authors: Hans
authors: H
authors: Rommelspacher
authors: Catrin
authors: C
authors: Wernicke
mesh_terms: D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics; D000437:Alcoholism / Q000235:genetics*; D016022:Case-Control Studies; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D017448:Receptors, Dopamine D2