Interestingly, the genetic effect of GABRA2 on percentage of alcohol dependence symptom, Impulsiveness and insula activation was observed in females and not in males. No difference for this genetic effect was observed between subjects with higher risk for AUD compared to low risk subjects. Enoch et al, has reported association of anxiety disorders (lifetime DSM-III-R anxiety disorders) in an haplotype containing the rs279858 G allele in women in a case-control sample of Plain Indians alcoholics 7. This sex difference may be explained by the effect of neurosteroids, such as progesterone, on the GABA system modulating an array of behaviors including anxiety 51. Prolonged exposure to progesterone increased anxiety-like behavior in female rats 52. In addition, several cross-sectional, longitudinal and ecological momentary assessment studies have found that the association between distress and alcohol consumption was greater in women than in men 53–55. This may suggest that GABRA2 genetic variation may differentially influence the negative affect component in impulsive behavior in women; this in turn is an additional risk factor for problem alcohol consumption. Our results suggest that the alcohol dependence GABRA2 G-G haplotype captures the genetic susceptibility for Impulsiveness driven by anxiety in females.
