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ToolsMódos, Dezső, Thomas, John P., Brooks-Warburton, Johanne, Poletti, Martina, Bohar, Balazs, Liu, Yufan, Madgwick, Matthew, Csabai, Luca, Kang, Wen Xin, Alexander-Dann, Benjamin, Zoufir, Azedine, Sudhakar, Padhmanand, Cozzetto, Domenico, Fazekas, David, Samarajiwa, Shamith, Carding, Simon R., Powell, Nicholas, Verstockt, Bram, Bender, Andreas and Korcsmaros, Tamas (2026) Decoding non-coding SNPs: systems genomics modelling dissects the heterogeneity of IBD. Molecular Systems Biology, 22 (2). pp. 259-280. ISSN 1744-4292
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Abstract
Genome-wide association studies have identified numerous susceptibility loci in complex diseases, such as chronic immune-mediated inflammatory disorders (IMIDs), yet their impact on pathomechanisms remains 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. 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 gene regulatory networks 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.
| Item Type: | Article |
|---|---|
| Additional Information: | Data availability: The computer code produced in this study are available in the following database: https://github.com/korcsmarosgroup/iSNP. The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44320-025-00169-3. |
| Uncontrolled Keywords: | inflammatory bowel disease,network propagation,precision medicine,single-nucleotide polymorphisms,systems genomics,information systems,general immunology and microbiology,general biochemistry,genetics and molecular biology,general agricultural and biological sciences,computational theory and mathematics,applied mathematics ,/dk/atira/pure/subjectarea/asjc/1700/1710 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 14 May 2026 15:16 |
| Last Modified: | 14 May 2026 15:16 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/103028 |
| DOI: | 10.1038/s44320-025-00169-3 |
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