Journal of inflammation research
Integrative Transcriptomic and Genetic Analysis Prioritizes IRF1 as a Candidate Regulatory Gene Associated with Ulcerative Colitis
Von Wang Y, Chen Y und Wu H.
Inhalt auf Englisch
Abstract
Background
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex and incompletely understood pathogenesis. This study aimed to prioritize candidate genes associated with UC and characterize their potential genetic and immune-related molecular context using an integrative transcriptomic and genetic framework.
Methods
Bulk transcriptomic analysis was first performed using the discovery cohort GSE87466. After duplicated gene symbols were collapsed by mean expression, differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify UC-related candidate genes. Candidate genes for downstream analyses were defined by the overlap between differentially expressed genes and genes within selected WGCNA core modules. An expression quantitative trait locus-based summary-data-based Mendelian randomization (SMR) framework integrating UC genome-wide association study data with blood-derived eQTL data was subsequently applied to prioritize putative gene-disease associations. Functional enrichment analysis, CIBERSORT-based immune infiltration analysis, single-gene gene set enrichment analysis, and single-cell RNA sequencing analyses were performed to characterize the biological context of the prioritized genes. Three independent transcriptomic cohorts were used for external validation, and a small DSS-induced colitis mouse experiment was used for exploratory experimental assessment.