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Jones and H.L. Bruce Graduate Fellowship","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"Tom Calhoon"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Differences in na\u00efve 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\n                  <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                  . 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\n                  <jats:italic>C. elegans<\/jats:italic>\n                  ortholog of protein kinase D,\n                  <jats:italic>dkf-2<\/jats:italic>\n                  , likely underlies the chromosome V QTL. Furthermore, lower alcohol sensitivity,\n                  <jats:italic>i<\/jats:italic>\n                  .\n                  <jats:italic>e<\/jats:italic>\n                  . resistance to intoxication, was conferred by\n                  <jats:italic>dkf-2<\/jats:italic>\n                  loss-of-function mutations. Protein kinase D might represent a conserved, druggable target to modify alcohol sensitivity with application towards AUD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Article summary<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.09.598102","type":"posted-content","created":{"date-parts":[[2024,6,9]],"date-time":"2024-06-09T16:25:13Z","timestamp":1717950313000},"source":"Crossref","is-referenced-by-count":0,"title":["Natural variation in protein kinase D modifies alcohol sensitivity in\n                  <i>Caenorhabditis elegans<\/i>"],"prefix":"10.64898","author":[{"given":"Benjamin L.","family":"Clites","sequence":"first","affiliation":[{"name":"Waggoner Center for Alcohol & Addiction Research, Center for Learning and Memory, Department of Neuroscience, The University of Texas at Austin, Austin TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke","family":"Frohock","sequence":"additional","affiliation":[{"name":"Waggoner Center for Alcohol & Addiction Research, Center for Learning and Memory, Department of Neuroscience, The University of Texas at Austin, Austin TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J.","family":"Koury","sequence":"additional","affiliation":[{"name":"Department of Biology, Johns Hopkins University, Baltimore MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluwatoyin C.","family":"Ogunbi","sequence":"additional","affiliation":[{"name":"Waggoner Center for Alcohol & Addiction Research, Center for Learning and Memory, Department of Neuroscience, The University of Texas at Austin, Austin TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya K.","family":"Mastronardo","sequence":"additional","affiliation":[{"name":"Cell, Molecular, Developmental Biology and Biophysics Graduate Program, Johns Hopkins University, Baltimore MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhuvan V.","family":"Kanna","sequence":"additional","affiliation":[{"name":"Waggoner Center for Alcohol & Addiction Research, Center for Learning and Memory, Department of Neuroscience, The University of Texas at Austin, Austin TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0229-9651","authenticated-orcid":false,"given":"Erik C.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Biology, Johns Hopkins University, Baltimore MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan T.","family":"Pierce","sequence":"additional","affiliation":[{"name":"Waggoner Center for Alcohol & Addiction Research, Center for Learning and Memory, Department of Neuroscience, The University of Texas at Austin, Austin TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026042414300701000_2024.06.09.598102v2.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.735399"},{"key":"2026042414300701000_2024.06.09.598102v2.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2012.01799.x"},{"issue":"1","key":"2026042414300701000_2024.06.09.598102v2.3","doi-asserted-by":"crossref","first-page":"bpz020","DOI":"10.1093\/biomethods\/bpz020","article-title":"A new method for measuring the size of nematodes using image processing","volume":"4","year":"2019","journal-title":"Biology Methods and Protocols"},{"issue":"5","key":"2026042414300701000_2024.06.09.598102v2.4","first-page":"346","article-title":"The role of the BK channel in ethanol response behaviors: evidence from model organism and human studies","volume":"9","year":"2014","journal-title":"Front. 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