Supplementary Material for: Genome-wide cross-trait analysis in European populations reveals shared genetic architecture of COPD and the allergy spectrum

Background: 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 (AR), atopic dermatitis (AD), 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.