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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Brooks-Warburton, Johanne 
Sudhakar, Padhmanand 
Madgwick, Matthew 
Thomas, John P 

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.

Description

Keywords

Algorithms, Colitis, Ulcerative, Genomics, Humans, Karyopherins, MicroRNAs, Polymorphism, Single Nucleotide

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
European Research Council (336159)
Wellcome Trust (100974/B/13/Z)