A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in a complex disease

Abstract

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.

Big data in IBD: big progress for clinical practice

“…This approach thereby provides a framework to identify key components and/or pathways which mediate the pathogenesis of the disease. Brooks et al identified different clusters of patients with UC using network footprints created by combining mutation data, protein–protein interaction networks and gene expression data 14…”

“…Brooks et al identified different clusters of patients with UC using network footprints created by combining mutation data, protein–protein interaction networks and gene expression data. 14 …”

Network Biology Approaches to Achieve Precision Medicine in Inflammatory Bowel Disease

“…The OmniPath database is particularly useful for generating cell signalling networks as it allows the user to not only access the intracellular PPI network of a cell but also GRNs and even the extracellular ligand-receptor networks from a myriad of databases ( Türei et al, 2021 ). Although examples of cell signalling networks have been limited in IBD thus far, recently we established a novel bioinformatic pipeline termed “iSNP”, to create a UC-specific cell signalling network from patient-derived SNP data ( Brooks et al, 2019 ). In this approach we focused on SNPs located within non-coding regions of the genome, which represent the vast majority of SNPs associated with UC.…”

“…However, recent breakthroughs made in cancer demonstrate that multi-layered networks which incorporate various omics data are likely to yield more powerful and translatable insights for complex diseases ( Du and Elemento, 2015 ). There is a paucity of such approaches in IBD to date, although the aforementioned studies by Jostins et al (2012) , Martin et al (2019) and Brooks et al (2019) demonstrate the potential of such methods. In addition, despite the exponential increase in transcriptomics and metatranscriptomics studies in IBD in the past decade, such datasets are often limited by low patient numbers.…”