Factors beyond KCNJ6 haplotype may contribute to these interpretations. It is possible that the sex of individual neurons might contribute to the results. However, in nearly all parameters tested, there was no difference by sex. scRNAseq identified only 6 genes as different by sex and 4 of these are encoded by sex chromosomes. Basal morphology (Fig. 3B, D) was unaffected by sex, but membrane capacitance (Fig. 3F.a, p = 2.6 × 10−4), induced APs (step, Fig. 3G.b, p = 0.012), and ethanol-treated membrane capacitance (Fig. 5D.a, p = 3.1 × 10−8) all reached significance, although it is difficult to interpret how sex interacts with neuronal function in this context. Finally, we chose to focus on homozygous haplotypes and extreme AUD diagnoses to enhance contrasts, however, additional studies might examine if heterozygotes would exhibit gene dosage effects or be rescued by the presence of the major alleles, similar to endophenotype studies with the original subjects [8].
