RYR3 was implicated in a GWAS of ethanol response (Joslyn et al., 2010) and our observed association may be driven by functional SNPs (GWAS3D analysis, Table 1). In C. elegans, loss of the single RyR gene unc-68 reduces initial sensitivity to ethanol (Figure 4E, F). This mutation would be predicted to decrease intracellular Ca2+. Consistent with this observation, we found that mutations in csq-1, which would be predicted to increase intracellular Ca2+ concentration, increase initial sensitivity (Supplementary Figure S7A). Mutations in the ether-a-go-go-related potassium channel gene unc-103, which has a genetic interaction with unc-68, also decrease sensitivity to ethanol (Supplementary Figure S7D). In Drosophila, reduction of function of the RyR gene blunts rapid tolerance (Supplementary Figure S8B).
