Abstract
Background Eosinophilic esophagitis (EoE) is an atopic disease driven in part by genetic susceptibility, but single-trait GWAS have identified a limited number of genome-wide significant risk loci. Objective To expand discovery of EoE genetic risk loci by leveraging shared genetic architecture with other atopic diseases and to develop a polygenic risk score (PRS) for EoE. Methods We performed a GWAS of 1,757 individuals with EoE and 14,467 population controls. We then applied multi-trait analysis of GWAS (MTAG), integrating EoE with other atopic disease GWAS (UK Biobank; >450,000 subjects). Functional analyses were used to nominate candidate EoE risk genes. PRS models derived from MTAG were compared with PRS derived from the EoE-only GWAS. An interactive tool (EGIDExpress) was developed to enable dataset queries and visualization. Results The EoE-only GWAS identified 11 independent risk variants across 8 loci (p < 5 × 10ˆ-8), including 3 novel loci. MTAG identified 33 independent EoE risk variants across 24 loci, including 14 novel loci. Functional studies nominated 90 candidate EoE risk genes, including genes implicating mechanisms beyond type 2 immunity. A PRS derived from MTAG outperformed a PRS derived from the EoE-only GWAS (OR 11.57 [95% CI, 6.90-19.40] for top vs bottom decile). Conclusion Leveraging shared atopic disease genetics via MTAG substantially expands the landscape of EoE risk loci and improves EoE polygenic risk prediction, underscoring shared genetic mechanisms across atopic diseases. We further provide a public resource (EGIDExpress) to advance the field.