Mendelian randomization analysis of the causal relationship between allergic rhinitis and depression and underlying mediation mechanisms.

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.