Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

Dirk S. Paul (), Andrew E. Teschendorff, Mary A.N. Dang, Robert Lowe, Mohammed I. Hawa, Simone Ecker, Huriya Beyan, Stephanie Cunningham, Alexandra R. Fouts, Anita Ramelius, Frances Burden, Samantha Farrow, Sophia Rowlston, Karola Rehnstrom, Mattia Frontini, Kate Downes, Stephan Busche, Warren A. Cheung, Bing Ge, Marie-Michelle Simon, David Bujold, Tony Kwan, Guillaume Bourque, Avik Datta, Ernesto Lowy, Laura Clarke, Paul Flicek, Emanuele Libertini, Simon Heath, Marta Gut, Ivo G Gut, Willem H. Ouwehand, Tomi Pastinen, Nicole Soranzo, Sabine E. Hofer, Beate Karges, Thomas Meissner, Bernhard O. Boehm, Corrado Cilio, Helena Elding Larsson, Åke Lernmark, Andrea K. Steck, Vardhman K. Rakyan, Stephan Beck and R. David Leslie ()
Additional contact information
Dirk S. Paul: Medical Genomics, UCL Cancer Institute, University College London
Andrew E. Teschendorff: CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences
Mary A.N. Dang: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Robert Lowe: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Mohammed I. Hawa: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Simone Ecker: Medical Genomics, UCL Cancer Institute, University College London
Huriya Beyan: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Stephanie Cunningham: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Alexandra R. Fouts: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine
Anita Ramelius: Lund University, Skåne University Hospital
Frances Burden: University of Cambridge, Cambridge Biomedical Campus
Samantha Farrow: University of Cambridge, Cambridge Biomedical Campus
Sophia Rowlston: University of Cambridge, Cambridge Biomedical Campus
Karola Rehnstrom: University of Cambridge, Cambridge Biomedical Campus
Mattia Frontini: University of Cambridge, Cambridge Biomedical Campus
Kate Downes: University of Cambridge, Cambridge Biomedical Campus
Stephan Busche: McGill University
Warren A. Cheung: McGill University
Bing Ge: McGill University
Marie-Michelle Simon: McGill University
David Bujold: McGill University
Tony Kwan: McGill University
Guillaume Bourque: McGill University
Avik Datta: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Ernesto Lowy: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Laura Clarke: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Paul Flicek: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
Emanuele Libertini: Medical Genomics, UCL Cancer Institute, University College London
Simon Heath: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Marta Gut: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Ivo G Gut: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST)
Willem H. Ouwehand: University of Cambridge, Cambridge Biomedical Campus
Tomi Pastinen: McGill University
Nicole Soranzo: University of Cambridge, Cambridge Biomedical Campus
Sabine E. Hofer: Medical University of Innsbruck
Beate Karges: RWTH Aachen University
Thomas Meissner: German Center for Diabetes Research (DZD)
Bernhard O. Boehm: Ulm University Medical Centre
Corrado Cilio: Lund University, Skåne University Hospital
Helena Elding Larsson: Lund University, Skåne University Hospital
Åke Lernmark: Lund University, Skåne University Hospital
Andrea K. Steck: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine
Vardhman K. Rakyan: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Stephan Beck: Medical Genomics, UCL Cancer Institute, University College London
R. David Leslie: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.

Date: 2016
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DOI: 10.1038/ncomms13555

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