Multi-trait Analysis of GWAS Expands Eosinophilic Esophagitis Genetic Susceptibility and Polygenic Risk Scores.
Authors: Trimarchi MP, Namjou-Khales B, Ben-Baruch Morgenstern N, Rochman M, Chen X, Osswald GA, Besse JA, Shook MS, Caldwell JM, Lape M, Shoda T, Weirauch MT, Ruffner MA, Constantine GM, Martin LJ, Kottyan LC, Rothenberg ME
Journal: Journal of Allergy and Clinical Immunology 2026
Paper of the Month – Selected and discussed by Francesca Racca
🎯 Study Aim
🔬 Methods
📊 Key Findings
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The EoE-specific GWAS identified 11 independent risk variants across 8 loci, 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, implicating mechanisms beyond type 2 immunity.
- MTAG-derived PRS outperformed PRS derived from the EoE-specific GWAS.
Additional findings
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One new male-specific locus was discovered.
🧠 Interpretation
These findings expand the EoE genetic risk loci landscape and highlight the substantial polygenic contribution to EoE susceptibility. Moreover, they confirm extensive shared mechanisms abetween EoE and topic diseases. In particular, these findings confirm calpain 14 as an EoE- specific susceptibility factor and the role of multiple genes implicated in the pathogenetic pathways shared between EoE and atopic diseases, including TSLP, TGFbeta, TNFalpha, IL-4, IL-13 and STAT6 signaling. This study also implicates genes involved in T cell selection, protease inhibition, epidermal differentiation, DNA damage response, and homing signals broadening the pathophysiology of EoE beyond the Type-2 inflammation, eosinophils and Th2 cells to encompass innate immunity, fibroblasts, epithelial cells, macrophages, ILC2 and Th17.
The validated PRS enables future genetic risk assessment.
⚠️ Critical Appraisal
- Limited reliability of atopic diseases diagnoses:
- Self-reported diagnosis of allergic rhinitis and atopic dermatitis were accepted for diagnosis in EoE cohorts
- Atopy diagnosis in UK Biobank relied on ICD codes
- IgE-mediated food allergy, the atopic comorbidity most strongly associated with EoE, was excluded due to lack of robust GWAS data
- Analysis restricted to patients of European ancestry