Genetic association of a GABA(A) receptor gamma2 subunit variant with severity of acute physiological dependence on alcohol.

The ultimate goal of quantitative trait locus (QTL) mapping is to identify the genes affecting complex traits. Using animal models, we recently identified QTLs on mouse Chromosomes (Chrs) 1, 4, and 11 affecting genetic predisposition to acute alcohol withdrawal. Among mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains, the locus identified on Chr 11 ( approximately 20 cM) accounted for 12% of the genetic variability in withdrawal liability. Candidate genes in proximity to this QTL encode the gamma2, alpha1, and alpha6 subunits of GABAA receptors. The present studies identify a polymorphism between the B6 and D2 strains in the gamma2 subunit gene, Gabrg2, and expand genotypic analysis to their BXD recombinant inbred strains. This polymorphism predicts a difference in amino acid sequence (Ala-11 vs. Thr-11) within the extracellular amino-terminal region of the gamma2 subunit. Analysis using BXD strain means for acute alcohol withdrawal severity suggests that the gamma2 subunit polymorphism is genetically correlated with alcohol withdrawal severity. This is the first report that QTL mapping for an alcohol-related trait has successfully led to the identification of a polymorphic candidate gene product that is genetically associated with the trait.