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bioRxiv · 10.1101/2024.06.09.598102

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

Clites, B. L.·Koury, E. J.·Andersen, E. C.·Pierce, J.
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Abstract

Differences in naive 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 summaryWe 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.

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Clites, B. L., Koury, E. J., Andersen, E. C., Pierce, J.. 2024-06-09. Natural variation in protein kinase D modifies alcohol sensitivity in Caenorhabditis elegans. https://doi.org/10.1101/2024.06.09.598102

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