Ruan Jingsheng, Yi Xinglin
Department of Thoracic, Jinshan Hospital of Fudan University, Fudan University, Shanghai, China.
Department of Respiratory and Critical Care Medicine, Third Military Medical University, Chongqing, China.
J Transl Med. 2025 Apr 15;23(1):445. doi: 10.1186/s12967-025-06465-8.
The intricate shared genetic architecture underlying allergic disorders-including allergic asthma, atopic dermatitis, contact dermatitis, allergic rhinitis, allergic conjunctivitis, allergic urticaria, anaphylaxis, and eosinophilic esophagitis-remains incompletely characterized.
Our study employed genomic structural equation modeling (Genomic SEM) to define the common factor representing the shared genetic architecture of allergic disorders. Coupled with diverse post-GWAS analytical methods, we aimed to discover susceptible loci and investigate genetic associations with external traits. Furthermore, we explored enriched genetic pathways, cellular layers, and genomic elements, and investigated putative plasma protein biomarkers. Polygenic risk score (PRS) analyses, leveraging our integrated GWAS data, were conducted to assess chromosomal-level risk associations for allergic disorders.
A well-fitted genomic SEM integrated GWAS data, revealing the shared genetic architecture of allergic disorders. We identified a total of 2038 genome-wide significant SNP loci (p < 5e-8), including 31 previously unreported loci. Fine-mapping of variants and gene sets pinpointed 2 causal variants and 31 candidate susceptible genes. Genetic correlation analyses further illuminated the shared genetic architecture underlying multiple traits, notably psychiatric disorders. Preliminary findings identified four putative causal plasma protein biomarkers.
Notably, this study presents the first comprehensive genetic characterization of allergic disorders through a GWAS analysis of an unmeasured composite phenotype, providing novel insights into shared etiological pathways across these conditions.
包括过敏性哮喘、特应性皮炎、接触性皮炎、过敏性鼻炎、过敏性结膜炎、过敏性荨麻疹、过敏反应和嗜酸性食管炎在内的过敏性疾病背后复杂的共享遗传结构仍未完全明确。
我们的研究采用基因组结构方程模型（Genomic SEM）来定义代表过敏性疾病共享遗传结构的共同因素。结合多种全基因组关联研究（GWAS）后的分析方法，我们旨在发现易感基因座并研究与外部性状的遗传关联。此外，我们探索了富集的遗传途径、细胞层和基因组元件，并研究了假定的血浆蛋白生物标志物。利用我们整合的GWAS数据进行多基因风险评分（PRS）分析，以评估过敏性疾病的染色体水平风险关联。
一个拟合良好的基因组SEM整合了GWAS数据，揭示了过敏性疾病的共享遗传结构。我们共鉴定出2038个全基因组显著的单核苷酸多态性（SNP）位点（p < 5e-8），其中包括31个先前未报道的位点。对变异体和基因集的精细定位确定了2个因果变异体和31个候选易感基因。遗传相关性分析进一步阐明了多种性状（尤其是精神疾病）背后的共享遗传结构。初步研究结果确定了四种假定的因果血浆蛋白生物标志物。
值得注意的是，本研究通过对未测量的复合表型进行GWAS分析，首次对过敏性疾病进行了全面的遗传特征描述，为这些疾病的共享病因途径提供了新的见解。
