Patient-Specific Regulatory Network Rewiring in Inflammatory Bowel Disease : How Genetic Polymorphisms Divert Incoming Signals and Contribute to Disease Pathogenesis

Background: Intestinal cells receive incoming signals from neighboring cells and microbial communities. Upstream signaling pathways transduce these signals to reach transcription factors (TFs) that regulate gene expression. In inflammatory bowel disease (IBD), most single nucleotide polymorphisms (SNPs) are in non-coding genomic regions containing TF binding sites. These SNPs can alter TF binding affinity, leading to regulatory shifts: TFs may lose or gain binding sites, causing a significant rewiring of the incoming signals regulating gene expression. Understanding this rewiring offers critical insights into the cellular mechanisms driving IBD pathogenesis. Methods: To investigate this rewiring, we developed a systems genomics pipeline and analyzed individual genotype data from 2636 IBD patients to infer the incoming signals affecting patient-specific gene regulatory networks. Our in silico approach predicted changes in the repertoire of TFs binding to genomic loci due to IBD-associated non-coding SNPs in each patient compared to healthy controls. By functionally annotating the TFs in disease and healthy states, we highlighted the rewiring of upstream signaling pathways that may arise due to IBDassociated SNPs. Results: We revealed that diverse non-coding SNP combinations in IBD patients lead to functional switches from healthy signals to disease-associated signals, capturing patient heterogeneity while uncovering common upstream regulators driving disease pathogenesis. Notably, rewired incoming signals belonged to key functional processes such as pro-inflammatory immune responses, epithelial barrier dysfunction, stress responses, wound healing, and antimicrobial defense pathways. Conclusions: In summary, this work highlights the importance of personalized investigation of signaling processes upstream of genetic polymorphisms to gain a more comprehensive understanding of IBD pathogenesis. Lay Summary By studying the genome of 2,636 people with inflammatory bowel disease, we mapped how subtle genetic changes can work together to disrupt the normal incoming signals acting on cells, triggering processes that lead to the disease. Key words:Single nucleotide polymorphisms, Inflammatory Bowel Disease, Systems genomics, Gene regulatory networks, Signalling pathways, Crohn's disease, Ulcerative colitis