Genetic Correlations and Causal Relationships Among Allergic Diseases: A Comprehensive Mendelian Randomization Study With Multiomic Mediation Analysis

BACKGROUND: Allergic diseases, including allergic asthma (AA), allergic rhinitis (AR), atopic dermatitis (AD), and allergic conjunctivitis (AC), often coexist. However, the specific inflammatory mediators driving their shared mechanisms remain unclear. This study explored causal relationships and identified multiomic mediators among allergic diseases using Mendelian randomization (MR). METHODS: Large-scale GWAS datasets from FinnGen and UK Biobank were analyzed. Linkage disequilibrium score regression (LDSC) and MR-robust adjusted profile scoring (MR-RAPS) assessed genetic correlations and causal links. Crucially, multivariable MR (MVMR) adjusted for classical type 2 inflammatory factors to isolate independent effects. A two-step MR framework evaluated the mediating roles of immune cells, metabolites, gut microbiota, and serum proteins. RESULTS: Six disease pairs (AA-AR, AA-AD, AR-AA, AR-AD, AD-AA, and AD-AR) showed robust causal relationships independent of type 2 inflammation markers. Mediation analyses identified key inflammatory mediators, including immune cell subsets (e.g., CD45 on granulocytes), plasma metabolites (e.g., pentose acid), gut microbiota (e.g., Bacteroides intestinalis), and notably, serum proteins such as ABHD12 and SEZ6L2. Pathway analyses highlighted cytokine-cytokine receptor interactions and lipid metabolism. CONCLUSIONS: This study maps a comprehensive causal network of allergic multimorbidity. We identified novel serum proteins and metabolic mediators beyond the classical type 2 inflammation axis, offering potential therapeutic targets for disrupting the inflammatory crosstalk between allergic diseases.