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

## TL;DR

This study identifies new genetic risk factors for eosinophilic esophagitis and improves risk prediction by combining data from multiple atopic diseases.

## Contribution

The study introduces a multi-trait GWAS analysis and a novel polygenic risk score for EoE, revealing new loci and biological pathways.

## Key findings

- A GWAS identified 11 independent genetic risk variants for EoE, including 3 new loci.
- A multi-trait analysis identified 33 independent EoE risk variants, including 14 novel loci.
- A polygenic risk score from MTAG showed a significantly higher risk of EoE compared to GWAS-only scores.

## Abstract

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 < 5×10−8), 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.