Polygenic risk scores for late smoking initiation associated with the risk of schizophrenia

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.

Polygenic Risk Scores Differentiating Schizophrenia From Bipolar Disorder Are Associated With Premorbid Intelligence in Schizophrenia Patients and Healthy Subjects

“…The demographic information of these participants is summarized in Table 1 . All these individuals participated in our previous studies ( Ohi et al, 2020a , 2020b ). The target sample was recruited from the Schizophrenia Non-Affected Relative Project ( Ohi et al, 2019 , 2020a , 2020b ).…”

“…All these individuals participated in our previous studies ( Ohi et al, 2020a , 2020b ). The target sample was recruited from the Schizophrenia Non-Affected Relative Project ( Ohi et al, 2019 , 2020a , 2020b ). All participants were of Japanese descent and had no biological first- or second-degree relatives.…”

“…All participants were of Japanese descent and had no biological first- or second-degree relatives. A detailed description of participant recruitment and diagnosis was provided previously ( Ohi et al, 2019 , 2020a , 2020b ). Briefly, each patient was diagnosed based on unstructured clinical interviews, medical records, and clinical conferences according to the criteria in the DSM-5.…”

“…A detailed description of the genotyping, quality control, and imputation procedures applied in the target sample was provided previously ( Ohi et al, 2020a , 2020b ). Briefly, venous blood was collected from the target participants, and genomic DNA was extracted from whole blood samples.…”

“…For the PGS analysis, SNPs with high imputation quality (>0.9) were retained. To remove SNPs that were in linkage disequilibrium, the SNPs in the target sample were pruned based on a pairwise r 2 threshold of 0.25 and a window size of 200 SNPs using PLINK v1.9 as described previously ( Ohi et al, 2020a , 2020b ). After pruning, 1 354 311 independent SNPs remained.…”