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

作者：Johanne Brooks-Warburton, Dezső Módos, Padhmanand Sudhakar, Matthew Madgwick, John P. Thomas, Balázs Bohár, Dávid Fazekas, Azedine Zoufir, Orsolya Kapuy, Máté Szalay-Bekő, Bram Verstockt, Lindsay J. Hall, Alastair J.M. Watson, Mark Tremelling, Miles Parkes, Severine A.R.A. Vermeire, Andreas Bender, Simon R. Carding, Tamas Douglas Korcsmaros · 发表于：Nature Communications · 年份：2022 · DOI：10.1038/s41467-022-29998-8 · 被引用次数：28 · 研究领域：Protein Tyrosine Phosphatases、RNA modifications and cancer、RNA Research and Splicing

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.