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Nat Commun. 2016 Nov 29;7:13555. doi: 10.1038/ncomms13555.

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

Author information

1
Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
2
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
3
CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
4
Statistical Cancer Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
5
The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
6
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
7
Department of Clinical Sciences, Lund University, Skåne University Hospital, SE-20502 Malmö, Sweden.
8
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
9
National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
10
British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
11
Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.
12
McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
13
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
14
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 4, 08028 Barcelona, Spain.
15
Universitat Pompeu Fabra, Plaça de la Mercè 10, 08002 Barcelona, Spain.
16
Human Genetics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
17
Department of Pediatrics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
18
Division of Endocrinology and Diabetes, RWTH Aachen University, 52074 Aachen, Germany.
19
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
20
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany.
21
Division of Endocrinology, Department of Internal Medicine I, Ulm University Medical Centre, 89081 Ulm, Germany.
22
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore.
23
Imperial College London, London SW7 2AZ, UK.

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.

PMID:
27898055
PMCID:
PMC5141286
DOI:
10.1038/ncomms13555
[Indexed for MEDLINE]
Free PMC Article

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