RT Journal Article
SR Electronic
T1 A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in a complex disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 692269
DO 10.1101/692269
A1 Johanne Brooks
A1 Dezso Modos
A1 Padhmanand Sudhakar
A1 David Fazekas
A1 Azedine Zoufir
A1 Orsolya Kapuy
A1 Mate Szalay-Beko
A1 Matthew Madgwick
A1 Bram Verstockt
A1 Lindsay Hall
A1 Alastair Watson
A1 Mark Tremelling
A1 Miles Parkes
A1 Severine Vermeire
A1 Andreas Bender
A1 Simon R. Carding
A1 Tamas Korcsmaros
YR 2019
UL http://biorxiv.org/content/early/2019/07/04/692269.abstract
AB We describe a novel precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to identify the exact mechanisms of how SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 377 UC patients, we mapped the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. Unsupervised clustering algorithms grouped these patient-specific networks into four distinct clusters based on two large disease hubs, NFKB1 and PKCB. Pathway analysis identified the epigenetic modification as common and the T-cell specific responses as differing signalling pathways in the clusters. By integrating individual transcriptomes in active and quiescent disease setting to the patient networks, we validated the impact of non-coding SNPs. The iSNP approach identified regulatory effects of disease-associated non-coding SNPs, and identified how pathogenesis pathways are activated via different genetic modifications.