Alcohol dependence is associated with a NMDA-receptor 2B gene variant

Ethanol-induced glutamatergic neurotransmission has been shown to mediate pathophysiological mechanisms central to the development of alcohol dependence. Ethanol leads to allosteric inhibition of NMDA-receptor activity, the degree of which is dependent on the subunit composition of the receptor. NMDA-receptor 2B (NR2B) is a subunit that confers a high sensitivity to ethanol-induced inhibition. We performed an association study of alcohol dependence and a single nucleotide polymorphism (SNP) of the NR2B subunit leading to a C to T exchange in the gene region encoding the carboxyl-terminal intracellular domain. 248 patients with alcohol dependence according to DSM IV criteria and 275 unrelated control subjects were included in the study. The results show that the risk of alcohol dependence is significantly higher for individuals possessing genotype CC as compared to CT or TT (P = 0.0006). Our linding is supported by the allele distribution, showing a significant association of the C-allele with alcohol dependence (P = 0.0235). Within the group of patients, we found a significant association of the CC-genotype with the fulfilled number of DSM-IV criteria for alcohol dependence (P = 0.0224). We did not find an association of NR2B-genotype and withdrawal-related symptoms, age of onset, sex and psychiatric comorbidity. Our finding is of potential relevance for clinical issues, such as the assessment of therapeutic response to anti-craving substances based on the NR2B genotype.