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

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.

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.

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.

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.