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

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
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.