Decoding non-coding SNPs: systems genomics modelling dissects the heterogeneity of IBD
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.
Authors
- Tamás Korcsmáros (ORCID: https://orcid.org/0000-0003-1717-996X)
- Dávid Fazekas (ORCID: https://orcid.org/0000-0001-7605-592X)
- Shamith Samarajiwa (ORCID: https://orcid.org/0000-0003-1046-0601)
- Balázs Bohár (ORCID: https://orcid.org/0000-0002-3033-5448)
- Johanne Brooks-Warburton (ORCID: https://orcid.org/0000-0003-1705-6476)
- Andreas Bender (ORCID: https://orcid.org/0000-0002-6683-7546)
- Martina Poletti (ORCID: https://orcid.org/0000-0002-0066-7687)
- Bram Verstockt (ORCID: https://orcid.org/0000-0003-3898-7093)
- Luca Csabai (ORCID: https://orcid.org/0000-0003-3669-0042)
- Matthew Madgwick (ORCID: https://orcid.org/0000-0002-7901-416X)
- Simon R. Carding (ORCID: https://orcid.org/0000-0002-2383-9701)
- Nick Powell (ORCID: https://orcid.org/0000-0003-3231-6950)
- Dezső Módos (ORCID: https://orcid.org/0000-0001-9412-6867)
- Azedine Zoufir (ORCID: https://orcid.org/0000-0001-8501-5348)
- Padhmanand Sudhakar (ORCID: https://orcid.org/0000-0003-1907-4491)
- Benjamin Alexander-Dann (ORCID: https://orcid.org/0000-0001-6703-0042)
- Domenico Cozzetto (ORCID: https://orcid.org/0000-0001-6752-5432)
- Yufan Liu (ORCID: https://orcid.org/0009-0000-1253-1798)
- John P. Thomas (ORCID: https://orcid.org/0000-0001-7495-4630)
- Wen-Xin Kang
Institutions
- Eötvös Loránd University (HU)
- University of East Anglia (GB)
- University of Hertfordshire (GB)
- MRC Laboratory of Molecular Biology (GB)
- Khalifa University of Science and Technology (AE)
- Iuliu Hațieganu University of Medicine and Pharmacy (RO)
- University of Cambridge (GB)
- Norwich Research Park (GB)
- Age UK (GB)
- HUN-REN Szegedi Biológiai Kutatóközpont (HU)
- Lister Hospital (GB)
- Hammersmith Hospital (GB)
- Daresbury Laboratory (GB)
- Quadram Institute (GB)
- Babeș-Bolyai University (RO)
- Stevenage Bioscience Catalyst (GB)
- Earlham Institute (GB)
- Sci-Tech Daresbury (GB)
- Institute of Biochemistry (HU)
- The London College (GB)
- Imperial College London (GB)
- KU Leuven (BE)
Publication Details
- Journal
- Molecular Systems Biology
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1038/s44320-025-00169-3
- Primary Topic
- Inflammatory Bowel Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00