Wei Jin, Zhang Meng, Qi Mengmeng, He Chang, Ma Shiyin, Sui Liutao, Mao Zhi, Zhu Xiaoyan, Pan Xudong
Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
Eur Arch Psychiatry Clin Neurosci. 2025 Jul 25. doi: 10.1007/s00406-025-02068-y.
A growing body of evidence suggests the relationship of depression with an increased risk of age-related diseases (ARDs). To further understand the genetically predicted causative connections, a Mendelian randomization (MR) approach was conducted.
Genetic variants associated with depression were employed as instrumental variables from the PGC and FinnGen consortium, respectively. GWAS summary data for 14 ARDs were derived from recently large consortia. We employed univariable and bidirectional MR analysis, and meta-analysis combining the results from two databases. Importantly, the potential mediation effects and mediated proportions of sleep and exercise traits were evaluated using a two-step mediation MR analysis. Finally, the robustness of all the MR results was confirmed using multiple sensitivity analyses.
In univariable MR analysis, results of combine effect showed that genetically linked depression was causally associated with a range of ARDs, including myocardial infarction (MI) (OR: 1.156, 95%CI: 1.038-1.288, p = 0.008), coronary atherosclerosis (CAS) (OR: 1.008, 95%CI: 1.004-1.013, p < 0.001), peripheral arteriosclerotic disease (OR: 1.002, 95%CI: 1.000-1.003, p = 0.020), obesity (OR: 1.028, 95%CI: 1.001-1.056, p = 0.044), type 2 diabetes (T2D) (OR: 1.112, 95%CI: 1.034-1.197, p = 0.004), and metabolic syndrome (OR: 1.204, 95%CI: 1.064-1.364, p = 0.003). Reverse analyses revealed the causal effect of obesity on depression (OR: 1.110, 95%CI: 1.070-1.152, p < 0.001). In mediation analyses, physical activity and/or sleep traits mediated the causal associations between depression and MI, CAS, and T2D. We further quantified the mediation effects. Sensitivity analyses supported these observations.
Depression is causally associated with MI, CAS, peripheral arteriosclerotic disease, obesity, T2D, and metabolic syndrome. Moreover, physical activity and sleep traits, either individually or in combination, appear to mediate the causal associations.
越来越多的证据表明抑郁症与年龄相关疾病（ARDs）风险增加之间存在关联。为了进一步了解基因预测的因果关系，我们采用了孟德尔随机化（MR）方法。
分别将与抑郁症相关的基因变异作为来自PGC和芬兰基因联盟的工具变量。14种ARDs的全基因组关联研究（GWAS）汇总数据来自最近的大型联盟。我们采用了单变量和双向MR分析，以及结合两个数据库结果的荟萃分析。重要的是，使用两步中介MR分析评估了睡眠和运动特征的潜在中介效应和中介比例。最后，通过多次敏感性分析证实了所有MR结果的稳健性。
在单变量MR分析中，合并效应结果显示，基因关联的抑郁症与一系列ARDs存在因果关系，包括心肌梗死（MI）（比值比：1.156，95%置信区间：1.038 - 1.288，p = 0.008）、冠状动脉粥样硬化（CAS）（比值比：1.008，95%置信区间：1.004 - 1.013，p < 0.001）、外周动脉硬化疾病（比值比：1.002，95%置信区间：1.000 - 1.003，p = 0.020）、肥胖（比值比：1.
