Clites Benjamin L, Frohock Brooke, Koury Emily J, Andersen Erik C, Pierce Jonathan T
Waggoner Center for Alcohol & Addiction Research, Center for Learning and Memory, Department of Neuroscience, University of Texas at Austin, Austin TX.
Department of Biology, Johns Hopkins University, Baltimore MD.
bioRxiv. 2024 Jun 9:2024.06.09.598102. doi: 10.1101/2024.06.09.598102.
Differences in naïve alcohol sensitivity between individuals are a strong predictor of later life alcohol use disorders (AUD). However, the genetic bases for 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 . We performed a genome-wide association study to identify loci that underlie natural variation in alcohol sensitivity. We identified five quantitative trait loci (QTL) and further show that variants in the ortholog of protein kinase D, , likely underlie the chromosome V QTL. We found that resistance to intoxication was conferred by loss-of-function mutations as well as partly by a PKD inhibitor in a -dependent manner. Protein kinase D might represent a conserved, druggable target to modify alcohol sensitivity with application towards AUD.
个体之间初始酒精敏感性的差异是晚年酒精使用障碍（AUD）的有力预测指标。然而，酒精敏感性的遗传基础（乙醇代谢之外）以及调节酒精敏感性的药理学方法仍知之甚少。我们使用高通量行为筛选来测量对酒精的急性行为敏感性，这是一种中毒模型，对象是一组超过150种线虫野生菌株的基因多样化群体。我们进行了全基因组关联研究，以确定酒精敏感性自然变异背后的基因座。我们鉴定出五个数量性状基因座（QTL），并进一步表明蛋白激酶D（PKD）直系同源物中的变体可能是第五条染色体QTL的基础。我们发现，功能丧失突变以及部分依赖于PKD的PKD抑制剂赋予了对中毒的抗性。蛋白激酶D可能是一个保守的、可药物化的靶点，可用于改变酒精敏感性，以治疗酒精使用障碍。
