Integrating multi-omics and GWAS to decode the pathogenesis and comorbidity landscape of hemophagocytic lymphohistiocytosis

Abstract Background Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome with unclear genetic mechanisms and high mortality, especially in children. The main objective of this study was to generate the first genome-wide association dataset for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) using Genomic Structural Equation Modeling (Genomic-SEM), and to dissect its genetic architecture, key cell types, pathogenic mechanisms, and candidate genes, thereby identifying novel biomarkers and therapeutic targets for this disease. Methods To address the lack of direct phenotypic GWAS data for EBV-HLH, we applied Genomic Structural Equation Modeling (Genomic-SEM) to synthesize summary statistics from five HLH-related traits, generating the first genome-wide association dataset for EBV-HLH. Integrative analyses with single-cell RNA sequencing, spatial transcriptomics, and multi-omics data were performed to dissect its genetic architecture and pathogenic mechanisms. Results We identified 14 lead SNPs with enrichment in lipid metabolic pathways. Among prioritized genes, YPEL2 was the most robustly validated by MAGMA, MTWAS, and spatial transcriptomic analyses, with AP2B1, MAU2, and GDPD1 as additional novel candidates. Plasmacytoid dendritic cells were pinpointed as the primary cell type driving genetic risk, while spatial transcriptomics revealed enriched signals in adipose tissue, lung, and other organs. Cell-specific Mendelian randomization confirmed causal links between autoimmune diseases and EBV-HLH in distinct immune cell subsets. Validation in patient samples and HLH mouse models demonstrated downregulated MAU2 expression in peripheral blood mononuclear cells and infiltrated macrophages. Conclusions Our findings uncover the polygenic basis and cell-type-specific regulatory networks of EBV-HLH, providing novel biomarkers and therapeutic targets for this devastating disease.