Trimarchi Michael P, Namjou-Khales Bahram, Morgenstern Netali Ben-Baruch, Rochman Mark, Chen Xiaoting, Osswald Garrett, Besse John, Shook Molly, Caldwell Julie, Lape Michael, Shota Tetsuo, Weirauch Matthew T, Ruffner Melanie, Constantine Gregory, Martin Lisa J, Kottyan Leah C, Rothenberg Marc E
Cincinnati Children's Hospital Medical Center.
Children's Hospital of Philadelphia.
Res Sq. 2025 May 16:rs.3.rs-6630283. doi: 10.21203/rs.3.rs-6630283/v1.
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), 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.
包括嗜酸性粒细胞性食管炎（EoE）在内的特应性疾病部分由遗传易感性驱动。我们对1757例EoE患者和14467名人群对照进行了全基因组关联研究（GWAS），确定了跨越8个EoE风险位点的11个独立遗传风险变异（p<5×10），包括3个新位点。对EoE和其他特应性疾病进行的全基因组关联研究多性状分析（MTAG），纳入了来自英国生物银行研究的超过450,000名受试者，确定了跨越24个位点的33个独立EoE遗传风险变异，包括14个新位点。功能研究提名了90个EoE候选基因，其中一些涉及2型免疫以外的意外发病机制。与仅从GWAS得出的多基因风险评分相比，MTAG得出的多基因风险评分显示EoE的高风险（最高与最低十分位数相比，OR为11.57[6.90-19.40]）。开发了一个交互式工具（EGIDExpress），用于数据集查询和可视化。这些发现为EoE的遗传风险和发病机制提供了更深入的见解，强调了EoE与常见特应性疾病的遗传相互作用，并提供了一个将推动过敏领域发展的公共资源。
