A notable success in GWAS of alcohol-related endophenotypes focused on frontal theta band event related oscillations (theta ERO). Event-related oscillations (EROs) are highly heritable neuroelectric correlates of cognitive processes that exhibit deficits in alcoholics as well as their offspring at high risk to develop alcoholism, and thus are a good endophenotype. Analyses in 117 families densely affected by alcohol dependence revealed genome-wide significant association of theta ERO with several SNPs in KCNJ6 (p= 4.7 × 10−10)71. KCNJ6 encodes a potassium inward rectifier channel, GIRK2, whose activation contributes to slow inhibitory postsynaptic potentials that modulate neuronal excitability, and therefore influences neuronal networks72, 73. KCNJ6 modulates opioid effects on analgesia and addiction in humans74; animal models have shown GIRK channels are directly activated by ethanol and are important effectors in both opioid- and ethanol-induced analgesia74, 75 and are considered a viable drug target.
