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Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

Author

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  • N. T. Ventham

    (Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh)

  • N. A. Kennedy

    (Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh)

  • A. T. Adams

    (Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh)

  • R. Kalla

    (Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh)

  • S. Heath

    (CNAG-CRG, Centro Nacional de Análisis Genómico, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST)
    Universitat Pompeu Fabra (UPF))

  • K. R. O'Leary

    (Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh)

  • H. Drummond

    (Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh)

  • D. C. Wilson

    (University of Edinburgh)

  • I. G. Gut

    (CNAG-CRG, Centro Nacional de Análisis Genómico, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST)
    Universitat Pompeu Fabra (UPF))

  • E. R. Nimmo

    (Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh)

  • J. Satsangi

    (Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh)

Abstract

Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.

Suggested Citation

  • N. T. Ventham & N. A. Kennedy & A. T. Adams & R. Kalla & S. Heath & K. R. O'Leary & H. Drummond & D. C. Wilson & I. G. Gut & E. R. Nimmo & J. Satsangi, 2016. "Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13507
    DOI: 10.1038/ncomms13507
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    Cited by:

    1. Dominik Aschenbrenner & Isar Nassiri & Suresh Venkateswaran & Sumeet Pandey & Matthew Page & Lauren Drowley & Martin Armstrong & Subra Kugathasan & Benjamin Fairfax & Holm H. Uhlig, 2024. "An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Tianyu Zhu & Huige Tong & Zhaozhen Du & Stephan Beck & Andrew E. Teschendorff, 2024. "An improved epigenetic counter to track mitotic age in normal and precancerous tissues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Antonella Fazio & Dora Bordoni & Jan W. P. Kuiper & Saskia Weber-Stiehl & Stephanie T. Stengel & Philipp Arnold & David Ellinghaus & Go Ito & Florian Tran & Berith Messner & Anna Henning & Joana P. Be, 2022. "DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Claudia Sala & Pietro Di Lena & Danielle Fernandes Durso & Andrea Prodi & Gastone Castellani & Christine Nardini, 2020. "Evaluation of pre-processing on the meta-analysis of DNA methylation data from the Illumina HumanMethylation450 BeadChip platform," PLOS ONE, Public Library of Science, vol. 15(3), pages 1-15, March.
    5. Han Zhang & Rahul Kalla & Jie Chen & Jianhui Zhao & Xuan Zhou & Alex Adams & Alexandra Noble & Nicholas T. Ventham & Judith Wellens & Gwo-Tzer Ho & Malcolm G. Dunlop & Jan Krzysztof Nowak & Yuan Ding , 2024. "Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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