Abstract
The gamma aminobutyric acid (GABA) system has been implicated in the susceptibility to develop alcohol dependence and in determining electroencephalogram (EEG) beta activity. The role of the GABA receptor alpha-2 gene (GABRA2) in human alcohol dependence was determined in a genetic and electrophysiological study. The study population comprised 586 white UK individuals with alcohol dependence but a very low prevalence of co-morbid drug dependence, and 603 ancestrally matched healthy controls. Genotyping for seven GABRA2 single nucleotide polymorphisms (SNPs), identified from the literature as positively associated with alcohol dependence, was performed with success rates of 90% or greater. EEGs were available in 32 selected patients who had been abstinent from alcohol for a minimum of 24 months and in 138 ancestrally matched healthy controls. None of the SNPs showed allelic or haplotypic association with alcohol dependence. All markers were in Hardy Weinberg equilibrium (HWE) in the controls. HWE for marker rs279841 in the alcohol dependent sample was p=0.0199 and combined p=0.0166. Linkage disequilibrium patterns appear to be very similar to that observed in the HapMap CEU data. A significantly higher prevalence of excess EEG fast activity was found in the patients (31 vs. 14%, p=0.018). A significant relationship was found between the presence of excess EEG fast activity and GABRA2 SNPs rs548583, rs279871 and rs279841. This allelic association study provides no evidence for an association between GABRA2 polymorphisms and alcohol dependence. However, a significant relationship was identified between GABRA2 and excess EEG fast activity. This dissociation of effect may reflect the fact that the EEG is a more direct marker of phenotypic GABRA2 expression than the more heterogeneous alcohol dependence phenotype.