We hypothesize that noncoding SNP variants in KCNJ6 alter neuronal excitability, potentially contributing directly or indirectly to network-level endophenotypes such as ERO. Furthermore, since ethanol interacts directly with GIRK2, we predict that excitability will be modulated by ethanol. To test these hypotheses, we evaluated a human neuron model system that includes variant genotypes, so that specific intergenic or noncoding sequences as well as genetic backgrounds influencing these functions would be preserved. Therefore, we selected subjects from the NIAAA/COGA Sharing Repository, four with the ERO-associated allelic variant in KCNJ6 and the presence of diagnosed alcohol dependence and four without the variant and unaffected for AUD and produced eight iPSC lines. iPSCs were reprogrammed into excitatory human neurons (iN) to investigate the potential contribution of the KCNJ6 SNPs to AUD diagnosis and the ERO power endophenotype (Fig. 1A). We found that neurons from KCNJ6 variant AUD-affected individuals demonstrated initial transcriptomic and morpho-physiological differences, mostly affecting excitability of the cells, which were paralleled by differences in GIRK2 expression levels. Ethanol exposure, conversely, induced GIRK2 expression, ameliorating differences in excitability. Moreover, by overexpressing KCNJ6
