{"doi":"10.1101/2024.06.09.598102","title":"Natural variation in protein kinase D modifies alcohol sensitivity in <i>Caenorhabditis elegans</i>","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":498327,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1345100,"name":"Brooke Frohock","orcid":null,"position":1,"is_corresponding":false},{"id":663138,"name":"Emily Koury","orcid":"0000-0001-7869-504X","position":2,"is_corresponding":false},{"id":290047,"name":"Erik C. Andersen","orcid":"0000-0003-0229-9651","position":3,"is_corresponding":false},{"id":385480,"name":"Jonathan T. Pierce","orcid":"0000-0002-9619-4713","position":4,"is_corresponding":false},{"id":1345101,"name":"Bhuvan V. Kanna","orcid":null,"position":5,"is_corresponding":false},{"id":1115111,"name":"Benjamin L Clites","orcid":null,"position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:09:38.543544Z","pmid":"38895441","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}