Khan Arshad H, Bagley Jared R, LaPierre Nathan, Gonzalez-Figueroa Carlos, Spencer Tadeo C, Choudhury Mudra, Xiao Xinshu, Eskin Eleazar, Jentsch James D, Smith Desmond J
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095.
Current address: Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.
bioRxiv. 2025 Mar 29:2024.12.04.626933. doi: 10.1101/2024.12.04.626933.
To identify genes that regulate the response to the potentially addictive drug cocaine, we performed a control experiment using genome-wide association studies (GWASs) and RNA-Seq of a panel of inbred and recombinant inbred mice undergoing intravenous self-administration of saline. A linear mixed model increased statistical power for analysis of the longitudinal behavioral data, which was acquired over 10 days. A total of 145 loci were identified for saline compared to 17 for the corresponding cocaine GWAS. Only one locus overlapped. Transcriptome-wide association studies (TWASs) using RNA-Seq data from the nucleus accumbens and medial frontal cortex identified and as significant for saline self-administration. Two other genes, and , were nominated based on proximity to loci for multiple endpoints or a locus regulating expression. All four genes have previously been implicated in locomotor activity, despite the absence of a strong relationship between saline taking and distance traveled in the open field. Our results indicate a distinct genetic basis for saline and cocaine self-administration, and suggest some common genes for saline self-administration and locomotor activity.
为了鉴定调控对潜在成瘾性药物可卡因反应的基因，我们利用全基因组关联研究（GWAS）和一组接受静脉注射生理盐水自我给药的近交系和重组近交系小鼠的RNA测序进行了一项对照实验。线性混合模型提高了对纵向行为数据的分析统计效力，这些数据是在10天内获取的。与相应的可卡因GWAS的17个位点相比，共鉴定出145个生理盐水相关位点。只有一个位点重叠。使用伏隔核和内侧前额叶皮质的RNA测序数据进行的全转录组关联研究（TWAS）确定了 和 对生理盐水自我给药具有显著性。另外两个基因 和 是根据与多个终点的位点接近度或调控表达的一个位点而被提名的。尽管在旷场实验中生理盐水摄入与行进距离之间没有很强的关系，但所有这四个基因此前都与运动活动有关。我们的结果表明生理盐水和可卡因自我给药有不同的遗传基础，并提示了一些与生理盐水自我给药和运动活动相关的共同基因。
