Abstract
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and allergic diseases share epithelial barrier dysfunction and immune imbalance, yet the shared genetic basis across the full allergy spectrum remains unclear. METHODS: We integrated large-scale genome-wide association study (GWAS) summary statistics from European populations for COPD and four allergic diseases - allergic asthma (AA), allergic rhinitis, atopic dermatitis, and allergic conjunctivitis (AC). Genome-wide genetic correlations were estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Cross-trait pleiotropy was tested with Pleiotropic Analysis under Composite Null Hypotheses (PLACO; p < 5 × 10-8). Functional Mapping and Annotation (FUMA), Bayesian colocalization, and Multi-Marker Analysis of GenoMic Annotation (MAGMA) were applied for locus annotation, causal inference, and gene-level prioritization, followed by pathway and tissue enrichment analyses. RESULTS: LDSC and HDL consistently revealed positive genetic correlations between COPD and allergic diseases (LDSC rg = 0.144-0.497; HDL rg = 0.141-0.605; all p < 1 × 10-3), exhibiting a gradient, with the strongest correlation for AA and the weakest for AC. We detected 70 pleiotropic loci, 24 with strong colocalization (PP.H4 ≥0.75), including recurrent hotspots at 2q12.1, 2q37.3, and 11q13.5. Gene-level analysis highlighted 172 pleiotropic genes (e.g., BACH2, IL18R1/IL1RL1/IL18RAP, IL1R1, ZGPAT) enriched for cytokine and inflammatory signaling, converging on the IL-1/IL-18/IL-33 axis and showing specificity in lung and immune tissues. CONCLUSION: This study provides the first systematic evidence, in individuals of European ancestry, of shared genetic architecture between COPD and multiple allergic diseases, supported by concordant LDSC/HDL genetic correlations and colocalized loci. Newly identified hotspots at 2q12.1 and 2q37.3 implicate the IL-1/IL-18/IL-33 pathway as a common mechanism in European populations, indicating pleiotropic variants affecting epithelial-immune interactions and nominating cytokine-related targets for translational investigation.