Objective:To investigate the bidirectional causal relationship between schizophrenia and suicide or intentional self-harm using a Mendelian randomization (MR) approach.Methods:Using pooled data from a large-scale genome-wide association study, genetic loci that were independent of each other and associated with schizophrenia and suicide or intentional self-harm in populations of European ancestry were selected as instrumental variables. The data for schizophrenia included 76 755 patients with schizophrenia and 243 649 controls. Data for suicide or intentional self-harm included 1 058 patients with suicide or intentional self-harm and 307 942 controls. The inverse variance weighting (IVW) and weighted median methods of MR analysis were used to explore the bidirectional causality of schizophrenia and suicide or intentional self-harm using the ratio of ratios ( OR) as an evaluation index. Heterogeneity between individual single nucleotide polymorphism (SNP) was assessed by Cochran′s Q test. Mendelian randomization polymorphism residuals and outliers (MR-PRESSO) were used to detect SNP outliers, and MR-Egger regression tests were performed to examine the horizontal pleiotropy of SNPs. A "leave-one-out" sensitivity analysis was performed to test whether the MR study was influenced by individual SNPs. Results:The IVW approach showed that schizophrenia increased the risk of suicide or intentional self-harm ( OR=1.297, 95% CI=1.154-1.457, P<0.001). In addition, the above relationship was confirmed in the weighted median ( OR=1.232, 95% CI=1.038-1.461, P=0.017). Conversely, suicide or intentional self-harm was not causally associated with schizophrenia ( OR=0.969, 95% CI=0.927—1.012, P=0.157), again confirmed by the weighted median method. The Cochran′s Q test, MR-PRESSO and MR-Egger regression tests did not show heterogeneity or horizontal pleiotropy between instrumental variables. The "leave-one-out" sensitivity analysis confirmed that no single SNP had a disproportionate effect on the overall outcome. Conclusion:Schizophrenia is significantly and causally associated with an increased risk of suicide or intentional self-harm.

Objective:To investigate the bidirectional causal relationship between schizophrenia and suicide or intentional self-harm using a Mendelian randomization (MR) approach.Methods:Using pooled data from a large-scale genome-wide association study, genetic loci that were independent of each other and associated with schizophrenia and suicide or intentional self-harm in populations of European ancestry were selected as instrumental variables. The data for schizophrenia included 76 755 patients with schizophrenia and 243 649 controls. Data for suicide or intentional self-harm included 1 058 patients with suicide or intentional self-harm and 307 942 controls. The inverse variance weighting (IVW) and weighted median methods of MR analysis were used to explore the bidirectional causality of schizophrenia and suicide or intentional self-harm using the ratio of ratios ( OR) as an evaluation index. Heterogeneity between individual single nucleotide polymorphism (SNP) was assessed by Cochran′s Q test. Mendelian randomization polymorphism residuals and outliers (MR-PRESSO) were used to detect SNP outliers, and MR-Egger regression tests were performed to examine the horizontal pleiotropy of SNPs. A "leave-one-out" sensitivity analysis was performed to test whether the MR study was influenced by individual SNPs. Results:The IVW approach showed that schizophrenia increased the risk of suicide or intentional self-harm ( OR=1.297, 95% CI=1.154-1.457, P<0.001). In addition, the above relationship was confirmed in the weighted median ( OR=1.232, 95% CI=1.038-1.461, P=0.017). Conversely, suicide or intentional self-harm was not causally associated with schizophrenia ( OR=0.969, 95% CI=0.927—1.012, P=0.157), again confirmed by the weighted median method. The Cochran′s Q test, MR-PRESSO and MR-Egger regression tests did not show heterogeneity or horizontal pleiotropy between instrumental variables. The "leave-one-out" sensitivity analysis confirmed that no single SNP had a disproportionate effect on the overall outcome. Conclusion:Schizophrenia is significantly and causally associated with an increased risk of suicide or intentional self-harm.