Studies on mice have identified more than 80 genes that affect alcohol preference drinking [59]. Pioneering work by Buck and colleagues identified three genomic regions on mouse chromosomes 1, 4 and 11 that influence acute alcohol withdrawal [71]. Through a succession of studies involving F2 intercrosses, construction of recombinant inbred lines, and interval-specific congenic strains [71-73], the gene encoding multiple PDZ domain protein (Mpdz) was identified as a quantitative trait gene for alcohol withdrawal symptoms. In humans, MPDZ does not demonstrate an association with alcohol-induced withdrawal seizures, but haplotype and single-SNP association analyses suggest a possible association with alcohol dependence [74] and alcohol consumption [65]. Another QTL on chromosome 1 was mapped to a 0.44 Mb interval containing 15 candidate genes, including Kcnj9. Kcnj9 encodes GIRK3, a subunit member of a family of G-protein-dependent inwardly rectifying K+ channels that mediate postsynaptic inhibitory effects of Gi/o-coupled receptors [75]. Kcnj9-null mutant mice show reduced withdrawal from pentobarbital, zolpidem and ethanol [76].
