Natural variation in protein kinase D modifies alcohol sensitivity in Caenorhabditis elegans

Differences in naive alcohol sensitivity among individuals are a strong predictor of later-life alcohol use disorders (AUD). However, the genetic basis of alcohol sensitivity (beyond ethanol metabolism) and pharmacological approaches to modulate alcohol sensitivity remain poorly understood. We used a high-throughput behavioral assay 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.