Genetic overlap between treatment-resistant schizophrenia and smoking initiation

Early detection of treatment-resistant schizophrenia (TRS) is of substantial clinical importance. While TRS is heritable, the associated genetic variants have been difficult to identify. Cigarette smoking is associated with non-response to antipsychotics, and smoking behavior and schizophrenia have a shared genetic basis. Thus, TRS may also have a shared genetic basis with smoking behavior. Here we aim to identify genetic variants associated with TRS, by leveraging overlapping genetic variants with smoking initiation to increase statistical power. We analyzed genome-wide data for TRS and smoking initiation with the conditional/conjunctional false discovery rate (cond/conjFDR) to identify shared loci, and LD score regression to determine genetic correlations. To investigate potential causal effects of shared loci, we performed Mendelian randomization (MR) analyses. Shared loci were mapped to genes, which were further investigated for enrichment of drug target genes. We observed a significant positive genetic correlation between TRS and smoking initiation (rg = 0.47 p = 0.0002). Leveraging the genetic overlap between TRS and smoking initiation, we identified four novel loci jointly associated with TRS and smoking initiation. The condFDR results improved polygenic prediction of TRS. MR showed putative evidence for a causal effect of genetic liability to TRS on smoking initiation. The functional genetic analyses showed that alpha-1-adrenergic receptors are likely involved in the pathophysiology of TRS and possibly related to the efficacy of clozapine versus other antipsychotic drugs. In conclusion, our results show that shared genetic mechanisms influence both TRS and smoking behavior, which provide new insights into the biological underpinnings of TRS.