过敏性鼻炎与抑郁症因果关系的孟德尔随机化分析及潜在中介机制

文献信息

中文摘要

背景： 流行病学研究已记录过敏性鼻炎（AR）与抑郁症（DE）之间的关联，但因果解释受到混杂因素和反向因果关系的限制。我们应用双向两样本孟德尔随机化来评估这种关联的方向和幅度，并探索候选通路。
方法： 汇总水平数据分别来自欧洲血统的2项AR GWAS（研究AR1：n = 112 583；研究AR2：n = 83 529）和2项DE GWAS（研究DE1：n = 484 598；研究DE2：n = 462 933）。独立的单核苷酸多态性（P < 5 × 10-8；LD r 2 < 0.001）作为工具变量。使用逆方差加权MR得出正向和反向估计，并以MR-Egger和加权中位数分析进行敏感性分析。采用两步框架估计通过睡眠时长（SD）和焦虑症状（ANX）的各自间接效应。多变量MR同时建模AR和8个额外特征——动态活动比率、低强度体力活动、中高强度活动、孤独感（LON）、神经质（NEU）、免疫球蛋白E（IgE）、白细胞介素-6和空腹胰岛素——以估计条件效应。使用MR-Egger截距、Cochran's Q和MR-PRESSO评估多效性和异质性。
结果： 在2个AR工具变量集和2个抑郁症结局中，AR的遗传易感性始终与抑郁症风险的轻度增加相关（IVW ORs 1.0105-1.0125），而反向分析未提供抑郁症易感性增加AR风险的证据。AR易感性与睡眠时长（β = 0.079；95% CI 0.005-0.153；P = 0.036）和焦虑症状（β = 0.031；95% CI 0.004-0.058；P = 0.025）存在名义关联，并与总IgE关联更强（β = 1.981；95% CI 1.200-2.762；P = 6.60 × 10-7）。通过睡眠时长（β = 0.005；95% CI -0.021至0.031；描述性比例47.7%）和焦虑（β = 0.003；95% CI -0.012至0.018；描述性比例24.2%）的各自间接效应不精确，且未合并。在MVMR中，孤独感与抑郁症的正向条件关联最强（OR = 1.243；95% CI 1.165-1.325；P = 3.40 × 10-11），而AR和IgE的条件估计为零。由于条件工具变量强度不可用，MVMR结果被解释为支持性通路证据。
结论： 在4个数据集配对中，AR的遗传易感性始终与抑郁症风险的轻度增加相关。尽管仅凭幅度不足以支持个体层面的临床决策，但一致的结果为AR-抑郁症关系增加了病因学证据。睡眠时长和焦虑仍是合理但未经确认的候选通路，而MVMR结果将孤独感列为需进一步验证的优先因素。总IgE更符合AR相关生物标志物，而非独立中介因素。

英文摘要

BACKGROUND: Epidemiological studies have documented an association between allergic rhinitis (AR) and depression (DE), but causal interpretation is limited by confounding and reverse causation. We applied bidirectional two-sample Mendelian randomization to assess the direction and magnitude of this association and to explore candidate pathways.
METHODS: Summary-level data were obtained separately from 2 AR GWAS (Study AR1: n = 112 583; Study AR2: n = 83 529) and 2 DE GWAS (Study DE1: n = 484 598; Study DE2: n = 462 933) of European ancestry. Independent single-nucleotide polymorphisms (P < 5 × 10-8; LD r 2 < 0.001) served as instruments. Forward and reverse estimates were derived using inverse-variance weighted MR, with MR-Egger and weighted median analyses for sensitivity. A two-step framework estimated separate indirect effects through sleep duration (SD) and anxiety symptoms (ANX). Multivariable MR simultaneously modeled AR and 8 additional traits-dynamic activity ratio, light-intensity physical activity, moderate-to-vigorous activity, loneliness (LON), neuroticism (NEU), immunoglobulin E (IgE), interleukin-6, and fasting insulin-to estimate conditional effects. Pleiotropy and heterogeneity were assessed using MR-Egger intercepts, Cochran's Q and MR-PRESSO.
RESULTS: Across 2 AR instrument sets and 2 depression outcomes, genetic liability to AR was consistently associated with a small increase in depression risk (IVW ORs 1.0105-1.0125), whereas reverse-direction analyses provided no evidence that depression liability increased AR risk. AR liability was nominally associated with sleep duration (β = 0.079; 95% CI 0.005-0.153; P = 0.036) and anxiety symptoms (β = 0.031; 95% CI 0.004-0.058; P = 0.025), and was more strongly associated with total IgE (β = 1.981; 95% CI 1.200-2.762; P = 6.60 × 10-7). The separate indirect effects through sleep duration (β = 0.005; 95% CI -0.021 to 0.031; descriptive proportion 47.7%) and anxiety (β = 0.003; 95% CI -0.012 to 0.018; descriptive proportion 24.2%) were imprecise and were not combined. In MVMR, loneliness showed the strongest positive conditional association with depression (OR = 1.243; 95% CI 1.165-1.325; P = 3.40 × 10-11), whereas the conditional AR and IgE estimates were null. Because conditional instrument strength was unavailable, MVMR findings were interpreted as supportive pathway evidence.
CONCLUSIONS: Genetic liability to AR was consistently associated with a small increase in depression risk across 4 dataset pairings. Although the magnitude alone is insufficient to support individual-level clinical decision-making, the concordant findings add etiological evidence for an AR-depression relationship. Sleep duration and anxiety remain plausible but unconfirmed candidate pathways, while the MVMR findings prioritize loneliness for further validation. Total IgE was more consistent with an AR-related biomarker than an independent mediator.