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, Tamas Korcsmaros

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
31 Downloads (Pure)

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.

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.

Original languageEnglish
Article number2299
Number of pages12
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 28 Apr 2022

Keywords

  • INFLAMMATORY-BOWEL-DISEASE
  • TRANSCRIPTION FACTOR-BINDING
  • RECEPTOR-TYROSINE KINASE
  • COMMUNITY STRUCTURE
  • MODEL
  • SUSCEPTIBILITY
  • POLYMORPHISMS
  • ASSOCIATION
  • METABOLISM
  • ACTIVATION

Cite this