title: Increased DNA methylation variability in type 1 diabetes across three immune effector cell types.
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.
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.|Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
authors.forename: Dirk S
authors.identifier: 0000-0002-8230-0116
authors.initials: DS
authors.lastname: Paul
authors.affiliation: 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.|Statistical Cancer Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Mary A N
authors.initials: MA
authors.lastname: Dang
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Lowe
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: Hawa
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Ecker
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Huriya
authors.initials: H
authors.lastname: Beyan
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cunningham
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Fouts
authors.affiliation: Department of Clinical Sciences, Lund University, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Ramelius
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Burden
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Farrow
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
authors.forename: Sophia
authors.initials: S
authors.lastname: Rowlston
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
authors.forename: Karola
authors.initials: K
authors.lastname: Rehnstrom
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Mattia
authors.identifier: 0000-0001-8074-6299
authors.initials: M
authors.lastname: Frontini
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.|McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Stephan
authors.initials: S
authors.lastname: Busche
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.|McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Warren A
authors.initials: WA
authors.lastname: Cheung
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.|McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.|McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Marie-Michelle
authors.initials: MM
authors.lastname: Simon
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.|McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: David
authors.initials: D
authors.lastname: Bujold
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.|McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.|McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Avik
authors.initials: A
authors.lastname: Datta
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Lowy
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Laura
authors.identifier: 0000-0002-5989-6898
authors.initials: L
authors.lastname: Clarke
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Paul
authors.identifier: 0000-0002-3897-7955
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Libertini
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 4, 08028 Barcelona, Spain.|Universitat Pompeu Fabra, Plaça de la Mercè 10, 08002 Barcelona, Spain.
authors.forename: Simon
authors.identifier: 0000-0002-9550-0897
authors.initials: S
authors.lastname: Heath
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 4, 08028 Barcelona, Spain.|Universitat Pompeu Fabra, Plaça de la Mercè 10, 08002 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 4, 08028 Barcelona, Spain.|Universitat Pompeu Fabra, Plaça de la Mercè 10, 08002 Barcelona, Spain.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.|Human Genetics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 0G1.|McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.|Human Genetics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Nicole
authors.identifier: 0000-0003-1095-3852
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Department of Pediatrics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Sabine E
authors.initials: SE
authors.lastname: Hofer
authors.affiliation: Division of Endocrinology and Diabetes, RWTH Aachen University, 52074 Aachen, Germany.|German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Karges
authors.affiliation: German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.|Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meissner
authors.affiliation: Division of Endocrinology, Department of Internal Medicine I, Ulm University Medical Centre, 89081 Ulm, Germany.|Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore.|Imperial College London, London SW7 2AZ, UK.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.affiliation: Department of Clinical Sciences, Lund University, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Corrado
authors.initials: C
authors.lastname: Cilio
authors.affiliation: Department of Clinical Sciences, Lund University, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Elding Larsson
authors.affiliation: Department of Clinical Sciences, Lund University, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Lernmark
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Steck
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Vardhman K
authors.initials: VK
authors.lastname: Rakyan
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Stephan
authors.identifier: 0000-0001-5290-2151
authors.initials: S
authors.lastname: Beck
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: R David
authors.initials: RD
authors.lastname: Leslie
mesh_terms: D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005312:Fetal Blood / Q000378:metabolism; D006801:Humans; D058977:Molecular Sequence Annotation; D013997:Time Factors; D014430:Twins, Monozygotic / Q000235:genetics