Natural variation in protein kinase D modifies alcohol sensitivity inCaenorhabditis elegans

Differences in naïve alcohol sensitivity among individuals are a strong predictor of later-life alcohol use disorders (AUD). However, the genetic bases of alcohol sensitivity (beyond ethanol metabolism) and pharmacological approaches to modulate alcohol sensitivity remain poorly understood. We used a high-throughput behavioral screen to measure acute behavioral sensitivity to alcohol, a model of intoxication, in a genetically diverse set of over 150 wild strains of the nematode Caenorhabditis elegans . We performed a genome-wide association study and identified five quantitative trait loci (QTL) that underlie natural variation in alcohol sensitivity. We validated that a variant in the conserved ubiquitin-like domain of a C. elegans ortholog of protein kinase D, dkf-2 , likely underlies the chromosome V QTL. Furthermore, lower alcohol sensitivity, i . e . resistance to intoxication, was conferred by dkf-2 loss-of-function mutations. Protein kinase D might represent a conserved, druggable target to modify alcohol sensitivity with application towards AUD. Article summary We investigated the genetic basis of differences in alcohol sensitivity, a key predictor of alcohol use disorder. We measured alcohol-induced behavioral changes in over 150 genetically diverse nematode strains. Using a genome-wide association study, which links genetic differences to traits, we identified five genomic regions associated with alcohol sensitivity. We then showed that variation in a gene encoding protein kinase D influences resistance to intoxication. These findings identify a conserved molecular pathway that affects alcohol sensitivity and highlight a potential target for intervention. They show how natural genetic variation can reveal mechanisms underlying complex, human-relevant traits.