Several pathways and key transcription factor modules were related to processes of DNA damage and repair processes in individuals with OUD. Based on our results and other findings11, we further investigated the relationship between DNA damage and OUD in specific cell types (Fig. 4a). In striatal neurons, we observed a significant enrichment of DNA damage markers in individuals with OUD (p = 0.046; linear regression t = 2.18; Fig. 4b). More specifically, a significant increase in DNA damage markers were found in interneurons of individuals with OUD (p = 0.035, linear regression t = 2.14; Figs. 4c, S6; Supplementary Data 1-S10). We further resolved the augmentation of DNA damage markers among striatal interneuron subtypes in OUD, except for PTHLH+ interneurons (Fig. S7, p < 0.025). Our findings suggest striatal neurons may incur DNA damage in response to opioids and other factors, such as stress, neuroinflammation, and hypoxia (Fig. 3), associated with OUD and opioid overdose. Interestingly, hypoxia pathways were significantly downregulated in OUD (Fig. 3d; Supplementary Data 1-S9), including decreased expression of genes that are activated in response to hypoxic
