Colocalization of association signals at nicotinic acetylcholine receptor genes between schizophrenia and smoking traits

Abstract Background Epidemiological data suggest that smoking may be a risk factor for schizophrenia (SCZ), but more evidence is needed. Two regions coding nicotinic acetylcholine receptor (nAchR) subunits, atCHRNA2 and the CHRNA5/A3/B4 cluster, were associated with SCZ in genome-wide association studies (GWAS). Additionally, a signal at CHRNA4 is near significance. CHRNA2 was also associated with cannabis use disorder (CUD). These regions were also associated with smoking behaviors. If tobacco is a risk factor, the GWAS signals at smoking behaviors and SCZ have to be due to the same causal variants, i.e. they have to colocalize, although colocalization does not necessarily imply causality. Here, we present colocalization analysis at these loci between SCZ and smoking behaviors. Methods The Bayesian approach implemented in coloc was used to check for posterior probability of colocalization versus independent signals at the three loci with some evidence of association with SCZ and smoking behaviors, using GWAS summary statistics. Colocalization was also assessed for positive control traits and CUD. Three different sensibility analyses were used to confirm the results. A visualization tool, LocusCompare, was used to facilitate interpretation of the coloc results. Results Evidence for colocalization of GWAS signals between SCZ and smoking behaviors was found for CHRNA2. Evidence for independent causal variants was found for the other two loci. CUD GWAS signal at CHRNA2 colocalizes with SCZ and smoking behaviors. Conclusions Overall, the results indicate that the association between some nAchR subunit genes and SCZ cannot be solely explained by their effect on smoking behaviors.