DataSheet_2_Bidirectional causal relational between frailty and mental illness: a two-sample Mendelian randomization study.csv

BackgroundFrailty has been associated with mental illness (MI) observational studies, but the causal relationship between these factors remains uncertain. We aimed to assess the bidirectional causality between frailty and MI by two-sample Mendelian randomization (MR) analyses.
MethodsTo investigate the causal relationship among them, summary statistics of frailty index (FI) and six types of MI: anxiety, depression, affective disorder, mania, schizophrenia, and obsessive-compulsive disorder (OCD) were included in this MR study. This MR analysis was performed using inverse variance weighting (IVW), MR-Egger regression, and weighted median. The stability of the results was evaluated using Cochran’s Q test, MR-Egger intercept test, Funnel Plots, and leave-one-out analysis.
ResultsGenetic predisposition to FI was significantly associated with increased anxiety (odds ratio [OR] = 1.62, 95% confidence interval [CI] 1.13-2.33, P = 8.18E-03), depression (OR = 1.88, 95% CI 1.30-2.71, P = 8.21E-04), affective disorder (OR = 1.70, 95% CI 1.28-2.27, P = 2.57E-04). However, our study findings do not demonstrate a causal relationship between FI and mania (OR = 1.02, 95% CI 0.99-1.06, P = 2.20E-01), schizophrenia (OR = 1.02, 95% CI 0.07-0.86, P = 9.28E-01). In particular, although the IVW results suggest a potential causal relationship between FI and OCD (OR = 0.64, 95% CI 0.07-0.86, P = 2.85E-02), the directions obtained from the three methods we employed ultimately show inconsistency. Therefore, the result must be interpreted with caution. The results of the reverse MR analysis indicated a statistically significant and causal relationship between anxiety (OR = 1.06, 95% CI 1.01-1.11, P = 2.00E-02), depression (OR = 1.14, 95% CI 1.04-1.26, P = 7.99E-03), affective disorder (OR = 1.15, 95% CI 1.09-1.21, P = 3.39E-07), and schizophrenia (OR = 1.02, 95% CI 1.01-1.04, P = 1.70E-03) with FI. However, our findings do not provide support for a link between mania (OR = 1.46, 95% CI 0.79-2.72, P = 2.27E-01), OCD (OR = 1.01, 95% CI 1.00-1.02, P = 2.11E-01) and an increased risk of FI.
ConclusionThe MR results suggest a potential bidirectional causal relationship between FI and anxiety, depression, and affective disorder. Schizophrenia was found to be associated with a higher risk of FI. The evidence was insufficient to support a causal relationship between Fl and other Ml. These findings offer new insights into the development of effective management strategies for frailty and MI.

背景 既往观察性研究已证实衰弱与精神疾病（mental illness, MI）存在关联，但二者间的因果关系仍未明确。本研究旨在通过双样本孟德尔随机化（two-sample Mendelian randomization, MR）分析，探究衰弱与精神疾病之间的双向因果关联。
方法 为明确二者间的因果关系，本MR研究纳入了衰弱指数（frailty index, FI）及六种精神疾病的汇总统计数据，分别为焦虑症、抑郁症、情感障碍、躁狂症、精神分裂症与强迫症（obsessive-compulsive disorder, OCD）。本MR分析采用逆方差加权（inverse variance weighting, IVW）、MR-Egger回归及加权中位数法开展。研究通过Cochran Q检验、MR-Egger截距检验、漏斗图以及留一法分析，对结果的稳定性进行评估。
结果 衰弱指数的遗传易感性与焦虑症（比值比[OR]=1.62，95%置信区间[CI] 1.13~2.33，P=8.18×10^-3）、抑郁症（OR=1.88，95%CI 1.30~2.71，P=8.21×10^-4）及情感障碍（OR=1.70，95%CI 1.28~2.27，P=2.57×10^-4）的发病风险升高显著相关。然而，本研究未发现衰弱指数与躁狂症（OR=1.02，95%CI 0.99~1.06，P=0.220）、精神分裂症（OR=1.02，95%CI 0.07~0.86，P=0.928）存在因果关联。特别地，尽管逆方差加权分析结果提示衰弱指数与强迫症可能存在因果关联（OR=0.64，95%CI 0.07~0.86，P=2.85×10^-2），但本研究采用的三种分析方法得到的效应方向最终并不一致，因此需谨慎解读该结果。反向MR分析结果显示，焦虑症（OR=1.06，95%CI 1.01~1.11，P=2.00×10^-2）、抑郁症（OR=1.14，95%CI 1.04~1.26，P=7.99×10^-3）、情感障碍（OR=1.15，95%CI 1.09~1.21，P=3.39×10^-7）及精神分裂症（OR=1.02，95%CI 1.01~1.04，P=1.70×10^-3）与衰弱指数存在具有统计学意义的因果关联。但本研究未发现躁狂症（OR=1.46，95%CI 0.79~2.72，P=0.227）、强迫症（OR=1.01，95%CI 1.00~1.02，P=0.211）与衰弱指数发病风险升高存在关联。
结论 本MR研究结果提示，衰弱指数与焦虑症、抑郁症及情感障碍之间存在潜在的双向因果关联。精神分裂症与衰弱指数发病风险升高相关。现有证据不足以支持衰弱指数与其余精神疾病间存在因果关联。本研究结果为制定衰弱与精神疾病的有效管理策略提供了新的视角。