Causal links between personality disorders and schizophrenia: A Mendelian randomization study

Although observational studies have suggested associations between personality disorders and schizophrenia, the causality of these relationships remains unclear. Determining whether personality disorders causally contribute to schizophrenia could inform early identification and preventive efforts. We performed two-sample Mendelian randomization (MR) analysis using large-scale Genome-wide Association Study data from populations of European ancestry. Because no single nucleotide polymorphism for personality disorders reached the conventional genome-wide significance threshold (P < 5 × 10-8), we sequentially relaxed the criteria (P < 5 × 10-7, P < 5 × 10-6, P < 5 × 10-5) until at least 10 instrumental variables were obtained. Ultimately, 11-95 single nucleotide polymorphism met the relaxed threshold (P < 5 × 10-5), all with F-statistics > 10, thus ensuring robust instrumental variables. The inverse variance weighted method served as our primary MR approach, supplemented by MR-Egger, weighted median, and MR Robust Adjusted Profile Score analyses, to minimize confounding, reverse causation, and weak instrument bias. Inverse variance weighted analysis revealed a significant causal association between genetically predicted personality disorders and schizophrenia (odds ratios = 1.190, 95% confidence intervals: 1.122-1.261, P = 5.51 × 10-9). Additionally, when examining a combined group of specific personality disorders, a similar causal effect was observed (odds ratios = 1.180, 95% confidence intervals: 1.033-1.345, P = .015). The sensitivity analyses showed no evidence of horizontal pleiotropy, thus supporting the robustness of these findings. Our study provides the first genetic evidence that personality disorders may have a causal influence on schizophrenia risk. These results highlight the importance of early screening and targeted interventions in individuals with personality disorders. Future research should expand to more diverse populations, employ dimensional diagnostic frameworks, and investigate the underlying biological and developmental pathways to refine the preventative and therapeutic strategies.