Cheng Gangming, Xu Lin, Li Hongjie, Cheng Yuan, Jiang Tao, Xu Qiong, Wang Jing
Department of Geriatric Medicine Ward II, Wuhan Mental Health Center, Wuhan, Hubei Province, China.
Department of Geriatric Medicine Ward II, Wuhan Hospital for Psychotherapy, Wuhan, Hubei Province, China.
Medicine (Baltimore). 2025 May 16;104(20):e42532. doi: 10.1097/MD.0000000000042532.
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.
尽管观察性研究表明人格障碍与精神分裂症之间存在关联，但这些关系的因果关系仍不明确。确定人格障碍是否因果性地导致精神分裂症，可为早期识别和预防工作提供依据。我们使用来自欧洲血统人群的大规模全基因组关联研究数据进行了两样本孟德尔随机化（MR）分析。由于人格障碍的单核苷酸多态性均未达到传统的全基因组显著性阈值（P < 5×10-8），我们依次放宽标准（P < 5×10-7、P < 5×10-6、P < 5×10-5），直到获得至少10个工具变量。最终，11 - 95个单核苷酸多态性达到放宽阈值（P < 5×10-5），所有这些单核苷酸多态性的F统计量均>10，从而确保了稳健的工具变量。逆方差加权法作为我们的主要MR方法，并辅以MR-Egger、加权中位数和MR稳健调整轮廓得分分析，以尽量减少混杂、反向因果关系和弱工具偏差。逆方差加权分析显示，遗传预测的人格障碍与精神分裂症之间存在显著的因果关联（优势比 = 1.190，95%置信区间：1.122 - 1.261，P = 5.51×10-9）。此外，在检查一组特定人格障碍的组合时，观察到了类似的因果效应（优势比 = 1.180，95%置信区间：1.033 - 1.345，P = 0.015）。敏感性分析未显示水平多效性的证据，从而支持了这些发现的稳健性。我们的研究提供了首个遗传学证据，表明人格障碍可能对精神分裂症风险有因果影响。这些结果突出了对人格障碍个体进行早期筛查和针对性干预的重要性。未来的研究应扩展到更多样化的人群，采用维度诊断框架，并研究潜在的生物学和发育途径，以完善预防和治疗策略。
