Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABAα6 receptors and the serotonin transporter in the level of response to alcohol:: A pilot study

Background: The vulnerability to alcohol dependence appears to be genetically influenced through a variety of mechanisms. One potentially genetically mediated channel may be a low level of response (LR) to alcohol, which has been seen in children of alcoholics and noted to predict future alcohol abuse and dependence. This pilot study uses a case and control genetic association approach to evaluate the possible role of five genotypes in both LR and alcoholism in informative subgroups of men with high and low LR scores documented 15 years earlier. Methods: As part of a larger study, 41 men, about 39 years old, were selected from among the first 113, completed 15-year follow-ups in a prospective study. The 17 subjects whose LRs at age 20 were in the lower third were compared on five polymorphisms of four genes with 24 men whose reactions to alcohol had been above the median, Results: The 14 men with the LL genotype of the serotonin transporter (5-HTT) polymorphism and the seven with the Pro/Ser genotype of the GAB(A alpha 6) polymorphism had demonstrated lower LR scores at about age 20, and had significantly higher proportions of alcoholics than the other genotypes for those loci. All four subjects with combined LL and Pro/Ser genotypes had developed alcoholism and demonstrated the lowest LR scores overall, There was no evidence that two polymorphisms of the 5-HT2A receptor gene and one of the 5-HT2C receptor gene were related to LR or alcoholism in this sample. Conclusions: These results are consistent with animal and human studies suggesting a possible role for genetic variation in the GABA(A alpha 6) and the serotonin transporter in the reaction to alcohol and the alcoholism risk. Biol Psychiatry 1999;45:647-651 (C) 1999 Society of Biological Psychiatry.