A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis.
Authors
Brooks-Warburton, Johanne
Sudhakar, Padhmanand
Madgwick, Matthew
Thomas, John P
Bohar, Balazs
Fazekas, David
Kapuy, Orsolya
Szalay-Beko, Mate
Tremelling, Mark
Bender, Andreas
Carding, Simon R
Publication Date
2022-04-28Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Nature Publishing Group UK
Volume
13
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Brooks-Warburton, J., Modos, D., Sudhakar, P., Madgwick, M., Thomas, J. P., Bohar, B., Fazekas, D., et al. (2022). A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-29998-8
Description
Funder: European research council grant number 336159
Funder: European Research Council Advanced Grant ERC-2015-AdG, 694679, CrUCCial
Funder: Academic Clinical Fellow supported by the National Institute of Health Research Health Education England (HEE) Genomics Education Programme
Funder: National Research, Development and Innovation Fund of Hungary under Grant FK 13426
Funder: Clinical Research Fund (KOOR), University Hospitals, Leuven, Belgium
Funder: Wellcome Trust Investigator Awards (100974/Z/13/Z and 220876/Z/20/Z)
Funder: Norwich Research Park Translational Fund NRP/TF/5.3
Abstract
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.
Keywords
Article, /631/553, /692/4020/1503/257/1389, /38, /139, /119, /141, /38/39, /45, /45/23, article
Sponsorship
European Research Council (336159)
Identifiers
s41467-022-29998-8, 29998
External DOI: https://doi.org/10.1038/s41467-022-29998-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336570
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.