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

Author

Listed:
  • Johanne Brooks-Warburton

    (Norwich Research Park
    The Quadram Institute Bioscience, Norwich Research Park
    University of Hertfordshire
    Lister Hospital)

  • Dezso Modos

    (Norwich Research Park
    The Quadram Institute Bioscience, Norwich Research Park
    University of Cambridge)

  • Padhmanand Sudhakar

    (Norwich Research Park
    The Quadram Institute Bioscience, Norwich Research Park
    Metabolism and Ageing)

  • Matthew Madgwick

    (Norwich Research Park
    The Quadram Institute Bioscience, Norwich Research Park)

  • John P. Thomas

    (Norwich Research Park
    The Quadram Institute Bioscience, Norwich Research Park
    Norfolk and Norwich University Hospitals)

  • Balazs Bohar

    (Norwich Research Park
    Eötvös Loránd University)

  • David Fazekas

    (Norwich Research Park
    Eötvös Loránd University)

  • Azedine Zoufir

    (University of Cambridge)

  • Orsolya Kapuy

    (Semmelweis University)

  • Mate Szalay-Beko

    (Norwich Research Park)

  • Bram Verstockt

    (Metabolism and Ageing
    University Hospitals Leuven, Department of Gastroenterology and Hepatology)

  • Lindsay J. Hall

    (The Quadram Institute Bioscience, Norwich Research Park
    University of East Anglia
    Technical University of Munich)

  • Alastair Watson

    (Norfolk and Norwich University Hospitals
    University of East Anglia)

  • Mark Tremelling

    (Norfolk and Norwich University Hospitals)

  • Miles Parkes

    (Addenbrooke’s Hospital, University of Cambridge)

  • Severine Vermeire

    (Metabolism and Ageing
    University Hospitals Leuven, Department of Gastroenterology and Hepatology)

  • Andreas Bender

    (University of Cambridge)

  • Simon R. Carding

    (The Quadram Institute Bioscience, Norwich Research Park
    University of East Anglia)

  • Tamas Korcsmaros

    (Norwich Research Park
    The Quadram Institute Bioscience, Norwich Research Park)

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.

Suggested Citation

  • Johanne Brooks-Warburton & Dezso Modos & Padhmanand Sudhakar & Matthew Madgwick & John P. Thomas & Balazs Bohar & David Fazekas & Azedine Zoufir & Orsolya Kapuy & Mate Szalay-Beko & Bram Verstockt & L, 2022. "A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29998-8
    DOI: 10.1038/s41467-022-29998-8
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    References listed on IDEAS

    as
    1. Yael Haberman & Rebekah Karns & Phillip J. Dexheimer & Melanie Schirmer & Judith Somekh & Ingrid Jurickova & Tzipi Braun & Elizabeth Novak & Laura Bauman & Margaret H. Collins & Angela Mo & Michael J., 2019. "Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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