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

Johanne Brooks-Warburton, Dezso Modos, Padhmanand Sudhakar, Matthew Madgwick, John P. Thomas, Balazs Bohar, David Fazekas, Azedine Zoufir, Orsolya Kapuy, Mate Szalay-Beko, Bram Verstockt, Lindsay J. Hall, Alastair Watson, Mark Tremelling, Miles Parkes, Severine Vermeire, Andreas Bender, Simon R. Carding () and Tamas Korcsmaros ()
Additional contact information
Johanne Brooks-Warburton: Norwich Research Park
Dezso Modos: Norwich Research Park
Padhmanand Sudhakar: Norwich Research Park
Matthew Madgwick: Norwich Research Park
John P. Thomas: Norwich Research Park
Balazs Bohar: Norwich Research Park
David Fazekas: Norwich Research Park
Azedine Zoufir: University of Cambridge
Orsolya Kapuy: Semmelweis University
Mate Szalay-Beko: Norwich Research Park
Bram Verstockt: Metabolism and Ageing
Lindsay J. Hall: The Quadram Institute Bioscience, Norwich Research Park
Alastair Watson: Norfolk and Norwich University Hospitals
Mark Tremelling: Norfolk and Norwich University Hospitals
Miles Parkes: Addenbrooke’s Hospital, University of Cambridge
Severine Vermeire: Metabolism and Ageing
Andreas Bender: University of Cambridge
Simon R. Carding: The Quadram Institute Bioscience, Norwich Research Park
Tamas Korcsmaros: Norwich Research Park

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29998-8

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