Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in inbred and recombinant inbred mice

To identify genetic pathways for addiction, we analyzed intravenous self-administration of cocaine or saline in a panel of 84 inbred and recombinant inbred mouse strains over 10 days. We integrated the behavior data with RNA-Seq data from the medial frontal cortex and nucleus accumbens from 41 strains. The self-administration of cocaine and saline showed distinct genetic bases. We maximized power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique significant loci were identified in the genome-wide association study (GWAS). A transcriptome-wide association study (TWAS) highlighted the Trpv2 ion channel as a key locus for cocaine self-administration from the GWAS. In addition, 17 genes supplementary to the GWAS were identified including Arhgef26, Slc18b1 and Slco5a1 . We found numerous instances where alternate splice site selection or RNA editing altered transcript abundance. Our work emphasizes the importance of Trpv2 , a known cannabinoid receptor, for the response to cocaine as well as identifying further relevant loci.