Sex differences in GABA_A receptor subunit transcript expression are mediated by genotype in subjects with alcohol-related cirrhosis of the liver

Male and female human subjects show contrasting propensities to misuse drugs of addiction, including alcohol. These differences lead to different psychological and neurological consequences, such as the likelihood of developing dependence. The pattern and extent of brain damage in alcohol-use disorder cases also varies with comorbid disease. To explore mechanisms that might underlie these outcomes, we used autopsy tissue to determine mRNA transcript expression in relation to genotype for two GABA_A receptor subunit genes. We used quantitative Real-Time PCR to measure GABRA6 and GABRA2 mRNA concentrations in dorsolateral prefrontal and primary motor cortices of alcohol-use disorder subjects and controls of both sexes with and without liver disease who had been genotyped for these GABA_A receptor subunit genes. Cirrhotic alcohol-use disorder cases had significantly higher expression of GABRA6 and GABRA2 transcripts than either controls or non-cirrhotic alcohol-use disorder cases. Differences were observed between sexes, genotypes and brain regions. We show that sex differences in subjects with GABRA6 and GABRA2 variants may contribute to differences in susceptibility to alcohol-use disorder and alcohol-induced cirrhosis.