Genetic landscape of morphine response in BXD recombinant inbred mice

Morphine is a potent analgesic and exhibits significant efficacy in alleviating severe pain. However, prolonged use can lead to drug dependency. Moreover, there are individual variations in response to and tolerance of morphine, indicating potential genetic regulation. Nevertheless, the mechanisms underlying these phenomena remain unclear. Therefore, we aimed to systematically dissect the genetic regulatory network for morphine response. We used quantitative trait locus mapping to identify genetic regions associated with morphine-related traits. Candidate genes for each locus were further filtered based on multiple criteria, including gene-trait association, cis-regulation, genetic variation, and potential function. The results showed that morphine response-related behavioral traits were significantly influenced by genetic background. Using the GEMMA and HK algorithms, we identified 18 genomic loci associated with dozens of morphine response-related traits. This includes loci previously studied on chromosome 10, together with a locus on chromosome 5 (0-20 Mb) identified in our analysis which showed the most association outside chromosome 10. Additionally, we identified six candidate functional genes (Cacna2d1, Myo7a, Elovl4, Oprm1, Cdk12, and Ccdc88c) that passed the filtering criteria. Oprm1 encodes the μ-opioid receptor, while Cacna2d1, Cdk12, and Elovl4 are closely associated with neurons. Myo7a and Ccdc88c may mediate anxiety and cognitive dysfunction caused by morphine dependence. Furthermore, Oprm1, Cacna2d1, and Ccdc88c are associated with opioid use disorders, nerve measurements, and brain volume in humans. In summary, our study describes the genetic regulation landscape of morphine response in BXD mice and identifies six candidate genes, providing valuable opportunities for further exploration.