Abstract
Patients with schizophrenia display characteristic smoking-related behaviors and genetic correlations between smoking behaviors and schizophrenia have been identified in European individuals. However, the genetic etiology of the association remains to be clarified. The present study investigated transethnic genetic overlaps between European-based smoking behaviors and the risk of Japanese schizophrenia by conducting polygenic risk score (PRS) analyses. Large-scale European genome-wide association study (GWAS) datasets (n = 24,114–74,035) related to four smoking-related intermediate phenotypes [(i) smoking initiation, (ii) age at smoking initiation, (iii) smoking quantity, and (iv) smoking cessation] were utilized as discovery samples. PRSs derived from these discovery GWASs were calculated for 332 Japanese subjects [schizophrenia patients, their unaffected first-degree relatives (FRs), and healthy controls (HCs)] as a target sample. Based on GWASs of European smoking phenotypes, we investigated the effects of PRSs on smoking phenotypes and the risk of schizophrenia in the Japanese population. Of the four smoking-related behaviors, the PRSs for age at smoking initiation in Europeans significantly predicted the age at smoking initiation (R2 = 0.049, p = 0.026) and the PRSs for smoking cessation significantly predicted the smoking cessation (R2 = 0.092, p = 0.027) in Japanese ever-smokers. Furthermore, the PRSs related to age at smoking initiation in Europeans were higher in Japanese schizophrenia patients than in the HCs and those of the FRs were intermediate between those of patients with schizophrenia and those of the HCs (R2 = 0.015, p = 0.015). In our target subjects, patients with schizophrenia had a higher mean age at smoking initiation (p = 0.018) and rate of daily smoking initiation after age 20 years (p = 0.023) compared with the HCs. A total of 60.6% of the patients started to smoke before the onset of schizophrenia. These findings suggest that genetic factors affecting late smoking initiation are associated with the risk of schizophrenia.
Highlights
The lifespan of patients with schizophrenia is 10–20 years shorter than that of the general population[1,2,3]
We found that genome-wide significant singlenucleotide polymorphisms (SNPs) on 15q25 shared between schizophrenia and smoking quantity contributed to a common pathophysiology underlying these phenotypes via altered CHRNA5 expression in the brain[23]
The present study investigated the effects of polygenic risk score (PRS) based on genome-wide association study (GWAS) of four Europeanbased smoking-related intermediate phenotypes [(i) smoking initiation, (ii) age at smoking initiation, (iii) smoking quantity, and (iv) smoking cessation] on smoking behaviors and the risk of schizophrenia in the Japanese population by PRS analyses as well
Summary
The lifespan of patients with schizophrenia is 10–20 years shorter than that of the general population[1,2,3]. Consistent with the comorbidity of schizophrenia and cigarette smoking behaviors, genetic correlations between the risk of schizophrenia, and higher smoking initiation, later age at smoking initiation and greater smoking quantity have been indicated by linkage disequilibrium score regression (LDSC) and polygenic risk score (PRS) analyses using European-based GWASs from the PGC and TAG27,28,31. These genetic correlations are restricted to findings derived from the same European-based GWAS datasets. The present study investigated the effects of PRSs based on GWASs of four Europeanbased smoking-related intermediate phenotypes [(i) smoking initiation, (ii) age at smoking initiation, (iii) smoking quantity, and (iv) smoking cessation] on smoking behaviors and the risk of schizophrenia in the Japanese population by PRS analyses as well
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
