Integrative Analysis of Whole Exome Sequencing and Gene Expression to Uncover Genetic Mechanisms in Inflammatory Bowel Disease

Background/Objectives: Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract. This study aimed to nominate candidate genes and pathways for IBD by integrating exome sequencing and gene expression data.

Methods

Whole-exome sequencing (WES) was performed on 10 patients with Crohn's disease (CD). Differential expression was analyzed with GEO2R in an independent RNA-seq dataset (GSE193677; 2490 biopsies from 1162 subjects). Immune-related differentially expressed genes (DEGs) were identified with ImmPort, hub genes by protein-protein interaction analysis, and enriched pathways with Enrichr. Missense variants were modeled with AlphaFold 3.

Results

WES identified 484 genes with rare coding variants in all 10 patients, and 732 genes were differentially expressed in CD or ulcerative colitis, 234 of them immune-related. Network, pathway, and database filtering prioritized ATM, CSF1R, FN1, and IL11, which together carry eight rare missense variants, with in silico predictions ranging from tolerated to deleterious. Enriched pathways included cytokine and interleukin signaling, and structural modeling predicted conformational changes.