DOP135 Patient-specific regulatory network rewiring in Inflammatory Bowel Disease: How genetic polymorphisms divert incoming signals and contribute to disease pathogenesis
Authors: Thomas J P , Bohar B , Verstockt B , Powell N , Korcsmaros T , Modos D 
Published: January 2025

Abstract

Background
Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), arises due to complex interactions between multiple environmental factors and genetic risk loci in the form of single nucleotide polymorphisms (SNPs)1. Many IBD-associated SNPs are located within non-coding genomic regions containing transcription factor (TF) binding sites, where they may cause regulatory shifts by altering TF binding affinity. TFs may lose or gain binding sites, causing a rewiring of the incoming signals acting on the genome2. Characterising these incoming signals could unveil critical insights into the upstream signalling mechanisms driving IBD which via non-coding genetic risk-loci impact downstream cellular processes. The identification of such incoming signals has been elusive with most studies to date evaluating the downstream impact of IBD-associated SNPs3.

Methods
We developed a novel systems genomics pipeline that individually analysed genotype data from 2636 IBD patients to infer the rewiring of incoming signals affecting gene regulatory networks. Our in silico approach predicted changes to the repertoire of TFs binding to genomic loci due to IBD-associated non-coding SNPs in each patient compared to the healthy state, where these SNPs may be absent. By functionally annotating the TFs in the disease and healthy states using the Gene Ontology database, we inferred the rewiring of upstream signalling pathways (Figure 1). Aggregating these patient-specific findings across the entire cohort allowed us to capture overarching shifts in the incoming signals in IBD that are likely to arise in the context of non-coding SNPs.

Results
This analysis revealed that 144 and 138 signals were gained or lost in UC patients and CD patients, respectively, compared to the healthy state. Among these, 95 signals were shared between UC and CD, indicating a significant overlap in the upstream signalling mechanisms underpinning both types of IBD. Notably, both diseases showed a net loss of incoming signals, emphasising a major rewiring and decrease of regulation by upstream signalling pathways. These signals belonged to broader categories representing immune response, cell stress response, epithelial barrier function, wound healing, and response to viral/bacterial infection (Figure 2).

Conclusion
This study highlights that IBD-associated SNPs contribute to disease pathogenesis not only through their downstream effects, but by rewiring the incoming signals which regulate gene expression. Our findings underscore the importance of investigating signalling processes upstream of genetic polymorphisms to gain a more comprehensive understanding of IBD pathogenesis.

References
1.Graham DB, Xavier RJ. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature. 2020;578(7796):527-539. doi:10.1038/s41586-020-2025-2
2.Cano-Gamez E, Trynka G. From GWAS to function: using functional genomics to identify the mechanisms underlying complex diseases. Front Genet. 2020;11:424. doi:10.3389/fgene.2020.00424
3.Brooks-Warburton J, Modos D, Sudhakar P, et al. A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis. Nat Commun. 2022;13(1):2299. doi:10.1038/s41467-022-29998-8