PT  - JOURNAL ARTICLE
AU  - Johanne Brooks
AU  - Dezso Modos
AU  - Padhmanand Sudhakar
AU  - David Fazekas
AU  - Azedine Zoufir
AU  - Orsolya Kapuy
AU  - Mate Szalay-Beko
AU  - Matthew Madgwick
AU  - Bram Verstockt
AU  - Lindsay Hall
AU  - Alastair Watson
AU  - Mark Tremelling
AU  - Miles Parkes
AU  - Severine Vermeire
AU  - Andreas Bender
AU  - Simon R. Carding
AU  - Tamas Korcsmaros
TI  - A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in a complex disease
AID  - 10.1101/692269
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 692269
4099  - http://biorxiv.org/content/early/2019/07/04/692269.short
4100  - http://biorxiv.org/content/early/2019/07/04/692269.full
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.