Cigarette smoking has been suggested to be associated with the risk of schizophrenia in observational studies. A significant causal effect of smoking on schizophrenia has been reported in European populations using the Mendelian randomization approach; however, no evidence of causality was found in participants from East Asia. Using Taiwan Biobank (TWBB), we conducted genome-wide association studies (GWAS) to identify susceptibility loci for smoking behaviors, including smoking initiation (N = 79,989) and the onset age (N = 15,582). We then meta-analyzed GWAS from TWBB and Biobank Japan (BBJ) with the total sample size of 245,425 for smoking initiation and 46,000 for onset age of smoking. The GWAS for schizophrenia was taken from the East Asia Psychiatric Genomics Consortium, which included 22,778 cases and 35,362 controls. We performed a two-sample Mendelian randomization to estimate the causality of smoking behaviors on schizophrenia in East Asia. In TWBB, we identified one locus that met genome-wide significance for onset age. In a meta-analysis of TWBB and BBJ, we identified two loci for smoking initiation. In Mendelian randomization, genetically predicted smoking initiation (odds ratio (OR) = 4.00, 95% confidence interval (CI) = 0.89–18.01, P = 0.071) and onset age (OR for a per-year increase = 0.96, 95% CI = 0.91–1.01, P = 0.098) were not significantly associated with schizophrenia; the direction of effect was consistent with European Ancestry samples, which had higher statistical power. These findings provide tentative evidence consistent with a causal role of smoking on the development of schizophrenia in East Asian populations.

Cigarette smoking has been suggested to be associated with the risk of schizophrenia (SCZ) in observational studies. A significant causal effect of smoking on SCZ has been reported in the European population using the Mendelian randomization (MR) approach; however, no evidence of causality was found in participants from East Asia (EAS). Using the Taiwan Biobank (TWBB, sample size up to 79,989), we conducted genome-wide association studies (GWAS) to identify susceptibility loci for smoking behavior, which included the initiation of smoking and the onset age. To maximize the power of genetic discovery in the EAS population, we meta-analyzed GWAS from the TWBB and Biobank Japan (BBJ, sample size up to 165,436) for smoking traits. The GWAS for SCZ was taken from the Asia Psychiatric Genomics Consortium, which included 22,778 cases and 35,362 controls. We performed a two-sample MR to estimate the causality of smoking behavior on SCZ in the EAS population. In TWBB, we identified one novel locus that met genome-wide significance for onset age. In a meta-analysis of TWBB and BBJ, we identified two novel loci for smoking initiation. In MR, a marginal significance was found for the causality of smoking initiation on SCZ (odds ratio (OR) = 4.00, 95% confidence interval (CI) = 0.89-18.01, P = 0.071). Later onset age for smoking was causally associated with a lower risk of SCZ (OR for a per-year increase in onset = 0.96, 95% CI = 0.91-1.01) with a marginal significance (P = 0.098).