GABRR1 and GABRR2, encoding the GABA-A receptor subunits ρ1 and ρ2, are associated with alcohol dependence

The genes encoding several GABA-A receptor subunits, including GABRA2, have been associated with alcoholism, suggesting that variations in gaba signaling contribute to risk. Therefore, as part of a comprehensive evaluationof the GABA receptor genes, weevaluated the potential association of GABRR1 and GABRR2, which encode the ρ1 and ρ2 subunits of the pentameric GABA-A/GABA-C receptors. GABRR1 and GABRR2 lie in a head to tail orientation spanning 137 kb on chromosome 6q14-16. Wegenotyped 73 single nucleotide polymorphisms (SNPs), covering both genes and extending 31 kb upstream of GABRR2 and 95kb downstream of GABRR1, in a sample of 1923 European Americans from 219 multiplex alcoholdependent families. Family-based association analyses demonstrated that SNPs in both GABRR1 and GABRR2 were significantly associatedwith alcohol dependence. Among the associated SNPs was rs282129, a coding SNP (Met430Thr) in GABRR2. Secondary analysis using amedian split for age of onset suggests that the association is strongest when the analysis is focused upon those with earlier onset of alcohol dependence. Haplotypes in each gene were signifi-cantly overtransmitted to familymembers whodid notmeet criteria for alcohol dependence (P<0.04), and a haplotype in GABRR2 was significantly overtransmitted to familymembers whomet a broader definition of alcoholism (P=0.002) as well as DSM-IV dependence (P=0.04).