Multi-trait Analysis of GWAS Expands Eosinophilic Esophagitis Genetic Susceptibility and Polygenic Risk Scores

Atopic diseases, including eosinophilic esophagitis (EoE), are driven in part by genetic susceptibility. We performed a genome-wide association study (GWAS) of 1,757 EoE and 14,467 population controls, identifying 11 independent genetic risk variants spanning 8 EoE risk loci (p < 5x10 ^− 8 ), including 3 new loci. A multi-trait analysis of GWAS (MTAG) of EoE and other atopic diseases including over 450,000 subjects from the UK Biobank study identified 33 independent EoE genetic risk variants spanning 24 loci, including 14 novel loci. Functional studies nominated 90 EoE candidate genes, some involved in unexpected pathoetiology beyond type 2 immunity. A polygenic risk score derived from the MTAG replicated high risk of EoE compared with PRS derived from GWAS alone (OR 11.57 [6.90–19.40] in the top vs. bottom decile). An interactive tool (EGIDExpress) was developed to enable dataset queries and visualization. These findings offer expanded insight into EoE genetic risk and pathoetiology, underscore the genetic interplay of EoE with common atopic diseases, and provide a public resource that will advance the allergy field.