Leveraging transcriptome-wide association studies identifies the relationship between upper respiratory flora and cell type-specific gene expression in severe respiratory disease

ObjectivesThe upper respiratory tract flora may influence host immunity and modulate susceptibility to viral respiratory infections. This study aimed to investigate the associations between upper respiratory tract flora and immune cells in severe ILI, identify specific microbial taxa and immune response pathways contributing to disease severity, and elucidate how flora influences ILI progression by modulating immune cell functions.MethodsHeritability of GWAS summary data was estimated using LDSC (v1.0.1). Gene-level genetic associations were analyzed with MAGMA. scRNA-seq data were integrated with genetic association data using scDRS. FUSION was used to construct cell type-specific expression quantitative trait locus models based on genotypes and scRNA-seq data from the onek1k project, which were combined with flora abundance-related GWAS data for a transcriptome-wide association study.ResultsFrom the LDSC analysis, data from 1195 severe ILI-associated GWASs with upper respiratory flora(h2 > 0.1) were included in subsequent analysis. TWAS identified 19 significant association pairs (Padj < 0.05), and 1226 differentially expressed genes between mild and severe ILI patients (Padj < 0.05 and | log2FC|>0.25). Functional enrichment analyses using GO, KEGG, and Reactome databases revealed that immune cells,such as CD4 + T effector memory cells, cDCs, NK cells, were enriched in multiple biological processes or pathways.ConclusionsThis study identified associations between severe ILI-related upper respiratory tract flora and cell type-specific gene expression, potentially explaining how differential flora influences ILI progression. CD16 + monocytes exhibited the most differentially expressed genes, followed by proliferating cells and cDCs, highlighting the significant role of immune cell-enriched pathways in ILI progression.