Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory gamma-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI). In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two SNPs and haplotypes were more likely to have alcohol dependence symptoms (rs279858 p = 0.01; rs279826 p = 0.05; haplotype p = 0.02) and higher NEO-PI-R Impulsiveness scores (rs279858 p = 0.016; rs279826 p = 0.012; haplotype p = 0.032) with a stronger effect in females (rs279858 p = 0.011; rs279826 p = 0.002; haplotype p = 0.006), all p values are corrected for family history and age. A subset of offspring from these families (n = 44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r2 = 0.4; p = 0.026) and loss (r2 = 0.38; p = 0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (ps’ < 0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.

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