title: Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.
abstract: Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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authors.affiliation: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.|Institute of Health Sciences, P.O. Box 5000, FI-90014 University of Oulu, Finland.|Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648, Singapore.
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authors.affiliation: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.|National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
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authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
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authors.affiliation: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.|Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technical University Munich, München, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
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authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Konstantin
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authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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authors.affiliation: Human Genetics Foundation-Torino, Torino, Italy.|Epidemiology and Public Health, Imperial College London, London, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
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authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.|The Institute of Cancer Research, Surrey SM2 5NG, UK.
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authors.affiliation: UCLH Bariatric Centre for Weight Loss, Weight Management and Metabolic and Endocrine Surgery, University College London Hospitals, Ground Floor West Wing, 250 Euston Road, London NW1 2PG, UK.|Centre for Obesity Research, Rayne Institute, Department of Medicine, University College London, London WC1E 6JJ, UK.
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.|Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
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authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
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authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.|Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
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authors.initials: CM
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authors.lastname: Milani
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Cardiology, 9700 RB Groningen, The Netherlands.|Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, The Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
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authors.initials: A
authors.lastname: Peters
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Hannover Unified Biobank, Hannover Medical School, Feodor-Lynen-Strasse 15, D-30625 Hanover, Germany.|Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hanover, Germany.
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authors.initials: T
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.|Biocenter Oulu, P.O. Box 5000, Aapistie 5A, FI-90014 University of Oulu, Finland.|Center for Life Course Epidemiology, Faculty of Medicine, P.O. Box 5000, FI-90014 University of Oulu, Finland.|Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, PO Box 20, FI-90220 Oulu, 90029 OYS, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: EPIGET Lab, Department of Clinical Sciences and Community Health, Università degli Studi di Milano and Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Pathology, National University Hospital, Singapore.
authors.forename: Richie
authors.initials: R
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authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.|Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.|Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.|Imperial College Healthcare NHS Trust, London W12 0HS, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.affiliation: Human Genetics Foundation-Torino, Torino, Italy.|Medical Sciences Department, University of Torino, Torino, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.|Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK.|Imperial College Healthcare NHS Trust, London W12 0HS, UK.
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kooner
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.|Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK.|Imperial College Healthcare NHS Trust, London W12 0HS, UK.|Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001769:Blood / Q000378:metabolism; D015992:Body Mass Index; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005060:Europe / Q000208:ethnology; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007194:India / Q000208:ethnology; D008297:Male; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics*; D050177:Overweight / Q000097:blood / Q000150:complications / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D005819:Genetic Markers