A genome-wide association meta-analysis identifies new eosinophilic esophagitis loci

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus marked by eosinophilic infiltration. Cumulative evidence indicates that the risk of EoE involves the complex interplay of both genetic and environmental factors. Because only a few genetic loci have been identified in EoE, the genetic underpinning of EoE remains largely elusive.

We sought to identify genetic loci associated with EoE.

Four EoE cohorts were genotyped using the Illumina single nucleotide polymorphism array platform, totaling 1,930 cases and 13,634 controls of European ancestry. Genotype imputation was performed with the Michigan Imputation Server using the Trans-Omics for Precision Medicine reference panel including whole-genome sequencing data from more than 100,000 individuals. Meta-analysis was conducted to identify potential novel genetic loci associated with EoE.

Our study identified 11 new genome-wide significant loci, of which 6 are common variant loci, including 5q31.1 (rs2106984, P = 4.16 × 10^-8; odds ratio [OR], 1.26, RAD50), 15q22.2 (rs2279293, P = 1.23 × 10^-10; OR, 0.69, RORA), and 15q23 (rs56062135, P = 2.91 × 10^-11; OR, 1.29, SMAD3), which have been previously associated with allergic conditions. Interestingly, a low-frequency synonymous mutation within the MATN2 gene was identified as the most significant single nucleotide polymorphism at the 8q22.1 locus. We also identified 5 sex-specific loci in the EoE cases, including an inflammatory bowel disease-associated locus at 9p24.1 (rs62541556, P = 4.4 × 10^-8; OR, 1.11, JAK2).

Our findings demonstrate shared genetic underpinnings between EoE and other immune-mediated diseases and provide novel candidate genes for therapeutic target identification and prioritization.