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

Brooks, J.; Modos, D.; Sudhakar, P.; Fazekas, D.; Zoufir, A.; Kapuy, O.; Szalay-Beko, M.; Madgwick, M.; Verstockt, B.; Hall, L.; Watson, A.; Tremelling, M.; Parkes, M.; Vermeire, S.; Bender, A.; Carding, S.; Korcsmaros, T.

doi:10.1101/692269

bioRxiv · 10.1101/692269

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

Brooks, J.·Modos, D.·Sudhakar, P.·Fazekas, D.·Zoufir, A.·Kapuy, O.·Szalay-Beko, M.·Madgwick, M.·Verstockt, B.·Hall, L.·Watson, A.·Tremelling, M.·Parkes, M.·Vermeire, S.·Bender, A.·Carding, S.·Korcsmaros, T.

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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.

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Brooks, J., Modos, D., Sudhakar, P., Fazekas, D., Zoufir, A., Kapuy, O., Szalay-Beko, M., Madgwick, M., Verstockt, B., Hall, L., Watson, A., Tremelling, M., Parkes, M., Vermeire, S., Bender, A., Carding, S., Korcsmaros, T.. 2019-07-04. A systems genomics approach to uncover patient-specific pathogenic pathways in a complex disease. https://doi.org/10.1101/692269

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