Genetic association of a GABA sub(A) receptor gamma sub(2) 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 ( similar to 20 cM) accounted for 12% of the genetic variability in withdrawal liability. Candidate genes in proximity to this QTL encode the gamma sub(2), alpha sub(1), and alpha sub(6) subunits of GABA sub(A) receptors. The present studies identify a polymorphism between the B6 and D2 strains in the gamma sub(2) 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 gamma sub(2) subunit. Analysis using BXD strain means for acute alcohol withdrawal severity suggests that the gamma sub(2) 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.