A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis

Brooks-Warburton, Johanne, Modos, Dezso, Sudhakar, Padhmanand, Madgwick, Matthew, Thomas, John P., Bohar, Balazs, Fazekas, David, Zoufir, Azedine, Kapuy, Orsolya, Szalay-Beko, Mate, Verstockt, Bram, Hall, Lindsay J. ORCID: https://orcid.org/0000-0001-8938-5709, Watson, Alastair ORCID: https://orcid.org/0000-0003-3326-0426, Tremelling, Mark, Parkes, Miles, Vermeire, Severine, Bender, Andreas, Carding, Simon R. and Korcsmaros, Tamas (2022) A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis. Nature Communications, 13 (1). ISSN 2041-1723

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We describe a precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 378 UC patients we map the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. With unsupervised clustering algorithms we group these patient-specific networks into four distinct clusters driven by PRKCB, HLA, SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH hubs. The pathway analysis identifies calcium homeostasis, wound healing and cell motility as key processes in UC pathogenesis. Using transcriptomic data from an independent patient cohort, with three complementary validation approaches focusing on the SNP-affected genes, the patient specific modules and affected functions, we confirm the regulatory impact of non-coding SNPs. iSNP identified regulatory effects for disease-associated non-coding SNPs, and by predicting the patient-specific pathogenic processes, we propose a systems-level way to stratify patients. Single Nucleotide Polymorphisms (SNPs) affect cellular regulatory networks, and SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Here the authors introduce iSNP, a precision medicine pipeline that combines genomics and network biology approaches to uncover patient specific pathways affected in complex diseases.

Item Type: Article
Additional Information: Funding Information: J.B.W. was funded by a Wellcome Trust Clinical Training Fellowship. D.M. and A.B. were funded by a European Research Council Starting Grant (336159). P.S. and S.V. were supported by the European Research Council Advanced Grant (ERC-2015-AdG, 694679, CrUCCial). The work of D.M., P.S., M.S.B., L.J.H., S.R.C. and T.K. were supported by the BBSRC Gut Microbes and Health Institute Strategic Programme BB/R012490/1 and its constituent projects BBS/E/F/000PR10353 and BBS/E/ F/000PR10355. L.J.H. is also funded by Wellcome Trust Investigator Awards (100974/Z/13/Z and 220876/Z/20/Z). A.W. is funded by the BB/K018256/1 grant. D.M., P.S. and T.K. were also supported by a BBSRC Core Strategic Programme Grant for Genomes to Food Security (BB/CSP1720/1) and its constituent work packages, BBS/E/T/000PR9819 and BBS/E/T/000PR9817. The work of J.B.W., T.K. and S.R.C. were supported by a Norwich Research Park Translational Fund grant (NRP/TF/5.3). O.K. is funded by the National Research, Development and Innovation Fund of Hungary under Grant FK 13426. B.V. is funded by the Clinical Research Fund (KOOR), University Hospitals, Leuven, Belgium. J.P.T. is funded by an Academic Clinical Fellow supported by the National Institute of Health Research (NIHR) and has been awarded funding through the Health Education England (HEE) Genomics Education Programme. M.M. is supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership (grant numbers BB/M011216/1 and BB/S50743X/1).
Uncontrolled Keywords: inflammatory-bowel-disease,transcription factor-binding,receptor-tyrosine kinase,community structure,model,susceptibility,polymorphisms,association,metabolism,activation,physics and astronomy(all),chemistry(all),biochemistry, genetics and molecular biology(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/3100
Faculty \ School:
Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 03 Oct 2022 11:31
Last Modified: 04 Mar 2024 18:13
URI: https://ueaeprints.uea.ac.uk/id/eprint/88808
DOI: 10.1038/s41467-022-29998-8


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