The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Zhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Department of Geriatrics, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang 310006, China.
Jiangxi Medicine Academy of Nutrition and Health Management, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
J Affect Disord. 2024 Sep 1;360:71-78. doi: 10.1016/j.jad.2024.05.105. Epub 2024 May 22.
Observational studies have shown that neuroticism is associated with frailty, but the causal relationship between them remains unclear.
A two-sample Mendelian randomization (MR) study was conducted to explore the bidirectional causal relationship between neuroticism (n = 380,506 for the primary analysis, n = 79,004 for the validation) and frailty (n = 175,226) using publicly available genome-wide association study data. The inverse variance weighted (IVW), weighted median, and MR-Egger were used to obtain the causal estimates. Findings were verified through extensive sensitivity analyses and validated using another dataset. Multivariable MR (MVMR) analysis was performed to estimate the direct causal effects with adjustment of potential confounders. Two-step MR technique was then conducted to explore the mediators in the causal effects of neuroticism on frailty.
Genetically-predicted higher neuroticism score was significantly correlated with higher frailty index (IVW beta: 0.53, 95%CI: 0.48 to 0.59, P = 9.3E-83), and genetically-determined higher frailty index was significantly associated with higher neuroticism score (IVW beta: 0.28, 95%CI: 0.21 to 0.35, P = 1.3E-16). These results remained robust across sensitivity analyses and were reproducible using another dataset. The MVMR analysis indicated that the causal relationships remained significant after adjusting for the potential confounding factors. Mediation analysis revealed that depression, years of schooling, and smoking were significantly mediated the causal effects of neuroticism on frailty.
A bidirectional causal relationship existed between neuroticism and frailty. Our findings suggested that early intervention and behavioral changes might be helpful to reduce the neuroticism levels and prevent the development of frailty.
观察性研究表明，神经质与虚弱有关，但它们之间的因果关系尚不清楚。
使用公开的全基因组关联研究数据，进行了两样本孟德尔随机化（MR）研究，以探索神经质（主要分析 n = 380506，验证 n = 79004）和虚弱（n = 175226）之间的双向因果关系。使用逆方差加权（IVW）、加权中位数和 MR-Egger 获得因果估计值。通过广泛的敏感性分析验证了结果，并使用另一个数据集进行了验证。进行多变量 MR（MVMR）分析，以调整潜在混杂因素后估计直接因果效应。然后进行两步 MR 技术，以探索神经质对虚弱的因果效应中的中介因素。
遗传预测的较高神经质评分与较高的虚弱指数显著相关（IVW beta：0.53，95%CI：0.48 至 0.59，P = 9.3E-83），而遗传确定的较高虚弱指数与较高神经质评分显著相关（IVW beta：0.28，95%CI：0.21 至 0.35，P = 1.3E-16）。这些结果在敏感性分析中仍然稳健，并可通过另一个数据集重现。MVMR 分析表明，在调整潜在混杂因素后，因果关系仍然显著。中介分析表明，抑郁、受教育年限和吸烟显著介导了神经质对虚弱的因果效应。
神经质与虚弱之间存在双向因果关系。我们的研究结果表明，早期干预和行为改变可能有助于降低神经质水平，预防虚弱的发生。
