Decoding non-coding SNPs: systems genomics modelling dissects the heterogeneity of IBD
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Genome-wide association studies have pinpointed numerous susceptibility loci in complex diseases like chronic immune-mediated inflammatory disorders (IMIDs), yet their impact on pathomechanisms remain poorly understood. Low effect sizes, polygenicity, and predominance within non-coding genomic regions remain major challenges to the functional interpretation of IMID-associated single nucleotide polymorphisms (SNPs). To address this, we present a novel systems genomics approach which models the cumulative impact of non-coding SNPs on downstream cellular signalling and gene regulatory networks (GRNs). Applying this to the prototypical chronic IMIDs of Crohn’s disease (CD) and ulcerative colitis (UC), both forms of inflammatory bowel disease (IBD), we individually analysed 2,636 patient genomes. Signals from non-coding SNPs were found to propagate towards well-established and novel CD- and UC-associated pathogenic pathways through the signalling and gene regulatory layers. The SNP-propagated GRNs stratified CD and UC patients into distinct clusters corresponding to cell type-specific gene dysregulation and potential therapeutic response. This approach bridges the gap between genotype and phenotype, laying the foundations for accelerating precision medicine in complex diseases.
Date Issued
2026-02-01
Date Acceptance
2025-10-27
Citation
Molecular Systems Biology, 2026, 22 (2), pp.259-280
ISSN
1744-4292
Publisher
Springer Nature
Start Page
259
End Page
280
Journal / Book Title
Molecular Systems Biology
Volume
22
Issue
2
Copyright Statement
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.
License URL
Identifier
10.1038/s44320-025-00169-3
Subjects
Precision Medicine
Single-nucleotide Polymorphisms
Systems Genomics
Network Propagation
Inflammatory Bowel Disease Subject Categories Digestive System
Genetics, Gene Therapy & Genetic Disease
Immunology
Publication Status
Published
Date Publish Online
2025-11-26