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Nature. 2017 Jan 5;541(7635):81-86. doi: 10.1038/nature20784. Epub 2016 Dec 21.

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Wahl S1,2,3, Drong A4, Lehne B5, Loh M5,6,7, Scott WR5,8, Kunze S1,2, Tsai PC9, Ried JS10, Zhang W5,11, Yang Y5, Tan S12, Fiorito G13,14, Franke L15, Guarrera S13,14, Kasela S16,17, Kriebel J1,2,3, Richmond RC18, Adamo M19, Afzal U5,11, Ala-Korpela M20,21,22, Albetti B23, Ammerpohl O24, Apperley JF25, Beekman M26, Bertazzi PA23, Black SL27, Blancher C28, Bonder MJ15, Brosch M29, Carstensen-Kirberg M3,30, de Craen AJ31, de Lusignan S32, Dehghan A33, Elkalaawy M19,34, Fischer K16, Franco OH33, Gaunt TR18, Hampe J29, Hashemi M19, Isaacs A33, Jenkinson A19, Jha S35, Kato N36, Krogh V37, Laffan M25, Meisinger C2, Meitinger T38,39,40, Mok ZY12, Motta V23, Ng HK12, Nikolakopoulou Z41, Nteliopoulos G25, Panico S42, Pervjakova N16,17, Prokisch H38,39, Rathmann W43, Roden M3,30,44, Rota F23, Rozario MA12, Sandling JK45,46, Schafmayer C47, Schramm K38,39, Siebert R24,48, Slagboom PE26, Soininen P20,21, Stolk L49, Strauch K10,50, Tai ES51,52,53, Tarantini L23, Thorand B2,3, Tigchelaar EF15, Tumino R54, Uitterlinden AG55, van Duijn C33, van Meurs JB49, Vineis P13,56, Wickremasinghe AR57, Wijmenga C15, Yang TP45, Yuan W9,58, Zhernakova A15, Batterham RL19,59, Smith GD18, Deloukas P45,60,61, Heijmans BT26, Herder C3,30, Hofman A33, Lindgren CM4,62, Milani L16, van der Harst P15,63,64, Peters A2,3,40, Illig T1,2,65,66, Relton CL18, Waldenberger M1,2, Järvelin MR67,68,69,70, Bollati V23, Soong R12,71, Spector TD9, Scott J8, McCarthy MI4,72,73, Elliott P5,74, Bell JT9, Matullo G13,14, Gieger C1,2, Kooner JS8,11,74, Grallert H1,2,3, Chambers JC5,11,74,75.

Author information

1
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
2
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
3
German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
5
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
6
Institute of Health Sciences, P.O. Box 5000, FI-90014 University of Oulu, Finland.
7
Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648, Singapore.
8
National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
9
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
10
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
11
Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK.
12
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
13
Human Genetics Foundation-Torino, Torino, Italy.
14
Medical Sciences Department, University of Torino, Torino, Italy.
15
University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, The Netherlands.
16
Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
17
Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia.
18
MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
19
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.
20
Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
21
NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
22
Computational Medicine, School of Social and Community Medicine, University of Bristol and Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
23
EPIGET Lab, Department of Clinical Sciences and Community Health, Università degli Studi di Milano and Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy.
24
Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel Campus, Kiel, Germany.
25
Centre for Haematology, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
26
Molecular Epidemiology, Leiden University Medical Center, Leiden, 2333 ZC, The Netherlands.
27
Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 0NN, UK.
28
High Throughput Genomics-Oxford Genomic Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
29
Medical Department 1, University Hospital of the Technical University Dresden, Dresden, Germany.
30
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
31
Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
32
Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7PX, UK.
33
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
34
Clinical and Experimental Surgery Department, Medical Research Institute, University of Alexandria, Hadara, Alexandria 21561, Egypt.
35
Department of Endocrinology, Diabetes and Obesity, Max Healthcare, New Delhi 110 017, India.
36
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo 1628655, Japan.
37
Epidemiology and Prevention Unit, Fondazione IRCSS Istituto Nazionale Tumori, Milano, Italy.
38
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
39
Institute of Human Genetics, Technical University Munich, München, Germany.
40
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
41
Vascular Biology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW3 6LY, UK.
42
Dipartmento Di Medicina Clinica E Chirurgia Federio II University, Naples, Italy.
43
Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
44
Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Hospital Düsseldorf, Düsseldorf, Germany.
45
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
46
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 751 44 Uppsala, Sweden.
47
Department of Visceral and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel Campus, Kiel, Germany.
48
Institute of Human Genetics, University Hospital of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany.
49
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
50
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
51
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
52
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore.
53
Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.
54
Cancer Registry and Histopathology Unit, 'Civile-M.P. Arezzo' Hospital, ASP 7, Ragusa, Italy.
55
Departments of Internal Medicine and Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
56
Epidemiology and Public Health, Imperial College London, London, UK.
57
Department of Public Health, Faculty of Medicine, University of Kelaniya, PO Box 6, Thalagolla Road, Ragama 11010, Sri Lanka.
58
The Institute of Cancer Research, Surrey SM2 5NG, UK.
59
Centre for Obesity Research, Rayne Institute, Department of Medicine, University College London, London WC1E 6JJ, UK.
60
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
61
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia.
62
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
63
University of Groningen, University Medical Center Groningen, Department of Cardiology, 9700 RB Groningen, The Netherlands.
64
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, The Netherlands.
65
Hannover Unified Biobank, Hannover Medical School, Feodor-Lynen-Strasse 15, D-30625 Hanover, Germany.
66
Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hanover, Germany.
67
Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
68
Biocenter Oulu, P.O. Box 5000, Aapistie 5A, FI-90014 University of Oulu, Finland.
69
Center for Life Course Epidemiology, Faculty of Medicine, P.O. Box 5000, FI-90014 University of Oulu, Finland.
70
Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, PO Box 20, FI-90220 Oulu, 90029 OYS, Finland.
71
Department of Pathology, National University Hospital, Singapore.
72
Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
73
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK.
74
Imperial College Healthcare NHS Trust, London W12 0HS, UK.
75
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

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 × 10-8 to 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 × 10-6 to 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.

PMID:
28002404
DOI:
10.1038/nature20784
[Indexed for MEDLINE]
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