Association of GABA_A receptors and alcohol dependence and the effects of genetic imprinting

GABA receptor genes have been postulated as candidates affecting the risk for alcoholism. The potential association between genes encoding five subunits of the GABA_A receptors and alcoholism (alcohol dependence) was analyzed in the multiplex alcoholic pedigrees collected by the Collaborative Study on the Genetics of Alcoholism (COGA) using family-based association tests. We found consistent, although weak, linkage disequilibrium between GABRB1 (located on chromosome 4) and alcoholism (P < 0.03). Genes encoding GABRA1 and GABRA6, on chromosome 5, did not provide evidence for association with alcoholism. GABRA5 and GABRB3, on chromosome 15, were reported to be expressed uniparentally from the paternal chromosome. Analyses of paternal transmission of alleles of GABRA5 provided evidence for association with alcoholism, particularly in the Caucasian population and with the stricter ICD-10 definition of alcoholism (P < 0.004). Evidence of association was also observed during paternal transmission with GABRB3 in the Caucasian population (P < 0.007). Maternal transmissions provided no evidence for association. These data are consistent with an association between the expressed alleles in the GABA_A-gene cluster on chromosome 15 and alcoholism that is modulated by genetic imprinting.