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dc.contributor.authorBrooks-Warburton, Johanne
dc.contributor.authorModos, Dezso
dc.contributor.authorSudhakar, Padhmanand
dc.contributor.authorMadgwick, Matthew
dc.contributor.authorThomas, John P
dc.contributor.authorBohar, Balazs
dc.contributor.authorFazekas, David
dc.contributor.authorZoufir, Azedine
dc.contributor.authorKapuy, Orsolya
dc.contributor.authorSzalay-Beko, Mate
dc.contributor.authorVerstockt, Bram
dc.contributor.authorHall, Lindsay J
dc.contributor.authorWatson, Alastair
dc.contributor.authorTremelling, Mark
dc.contributor.authorParkes, Miles
dc.contributor.authorVermeire, Severine
dc.contributor.authorBender, Andreas
dc.contributor.authorCarding, Simon R
dc.contributor.authorKorcsmaros, Tamas
dc.date.accessioned2022-05-30T15:03:02Z
dc.date.available2022-05-30T15:03:02Z
dc.date.issued2022-04-28
dc.identifier.issn2041-1723
dc.identifier.other35484353
dc.identifier.otherPMC9051123
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337611
dc.description.abstractWe 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.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101528555
dc.sourceessn: 2041-1723
dc.subjectHumans
dc.subjectColitis, Ulcerative
dc.subjectKaryopherins
dc.subjectMicroRNAs
dc.subjectGenomics
dc.subjectPolymorphism, Single Nucleotide
dc.subjectAlgorithms
dc.titleA systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis.
dc.typeArticle
dc.date.updated2022-05-30T15:03:02Z
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume13
dc.identifier.doi10.17863/CAM.85020
dcterms.dateAccepted2022-04-06
rioxxterms.versionofrecord10.1038/s41467-022-29998-8
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidModos, Dezso [0000-0001-9412-6867]
dc.contributor.orcidZoufir, Azedine [0000-0001-8501-5348]
dc.contributor.orcidVerstockt, Bram [0000-0003-3898-7093]
dc.contributor.orcidHall, Lindsay J [0000-0001-8938-5709]
dc.contributor.orcidWatson, Alastair [0000-0003-3326-0426]
dc.contributor.orcidParkes, Miles [0000-0002-6467-0631]
dc.contributor.orcidVermeire, Severine [0000-0001-9942-3019]
dc.contributor.orcidKorcsmaros, Tamas [0000-0003-1717-996X]
dc.identifier.eissn2041-1723
pubs.funder-project-idEuropean Research Council (336159)
cam.issuedOnline2022-04-28


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International