Downstream analyses prioritized genes and drug candidates that could be used for follow-up mechanistic studies in model organisms. Specifically, we identified “core” genes that could be “pleiotropic hotspots” associated with multiple traits. One was glutathione peroxidase-1 (GPX1), which is involved in oxidative stress. Intriguingly, it has been reported that glutathione peroxidase-1 protects against lung inflammation induced by smoking in mice, and agents that mimic this action (e.g., ebselen), which restore GPX1 activity in situations of extreme oxidative stress, can protect from lung inflammation induced by smoking.53 Another was GMPPB, which has been associated with accelerated lung aging and e-cigarette smoking.54 NT5C2 is involved in maintaining cellular nucleotide balance, and was associated with schizophrenia55 and smoking behaviors in an exome-wide association study.56 These genes showed a consistent association based on colocalization analyses (here and previously57), suggesting that they could confer TUD risk by modulating regulated gene expression and protein abundance in the brain.
