Letter | Published:

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

Nature volume 541, pages 8186 (05 January 2017) | Download Citation

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 disturbances1,2. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation3,4,5,6, a key regulator of gene expression and molecular phenotype7. 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.

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Acknowledgements

Detailed acknowledgments are provided in the Supplementary Information.

Author information

Author notes

    • Simone Wahl
    • , Alexander Drong
    • , Benjamin Lehne
    • , Marie Loh
    •  & William R. Scott

    These authors contributed equally to this work.

    • Anton J. M. de Craen

    Deceased.

    • Jordana T. Bell
    • , Giuseppe Matullo
    • , Christian Gieger
    • , Jaspal S. Kooner
    • , Harald Grallert
    •  & John C. Chambers

    These authors jointly supervised this work.

Affiliations

  1. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany

    • Simone Wahl
    • , Sonja Kunze
    • , Jennifer Kriebel
    • , Thomas Illig
    • , Melanie Waldenberger
    • , Christian Gieger
    •  & Harald Grallert
  2. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    • Simone Wahl
    • , Sonja Kunze
    • , Jennifer Kriebel
    • , Christa Meisinger
    • , Barbara Thorand
    • , Annette Peters
    • , Thomas Illig
    • , Melanie Waldenberger
    • , Christian Gieger
    •  & Harald Grallert
  3. German Center for Diabetes Research (DZD), München-Neuherberg, Germany

    • Simone Wahl
    • , Jennifer Kriebel
    • , Maren Carstensen-Kirberg
    • , Michael Roden
    • , Barbara Thorand
    • , Christian Herder
    • , Annette Peters
    •  & Harald Grallert
  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

    • Alexander Drong
    • , Cecilia M. Lindgren
    •  & Mark I. McCarthy
  5. Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK

    • Benjamin Lehne
    • , Marie Loh
    • , William R. Scott
    • , Weihua Zhang
    • , Youwen Yang
    • , Uzma Afzal
    • , Paul Elliott
    •  & John C. Chambers
  6. Institute of Health Sciences, P.O. Box 5000, FI-90014 University of Oulu, Finland

    • Marie Loh
  7. Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore 138648, Singapore

    • Marie Loh
  8. National Heart and Lung Institute, Imperial College London, London W12 0NN, UK

    • William R. Scott
    • , James Scott
    •  & Jaspal S. Kooner
  9. Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1 7EH, UK

    • Pei-Chien Tsai
    • , Wei Yuan
    • , Tim D. Spector
    •  & Jordana T. Bell
  10. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    • Janina S. Ried
    •  & Konstantin Strauch
  11. Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK

    • Weihua Zhang
    • , Uzma Afzal
    • , Jaspal S. Kooner
    •  & John C. Chambers
  12. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    • Sili Tan
    • , Zuan Yu Mok
    • , Hong Kiat Ng
    • , Michelle Ann Rozario
    •  & Richie Soong
  13. Human Genetics Foundation—Torino, Torino, Italy

    • Giovanni Fiorito
    • , Simonetta Guarrera
    • , Paolo Vineis
    •  & Giuseppe Matullo
  14. Medical Sciences Department, University of Torino, Torino, Italy

    • Giovanni Fiorito
    • , Simonetta Guarrera
    •  & Giuseppe Matullo
  15. University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, The Netherlands

    • Lude Franke
    • , Marc-Jan Bonder
    • , Ettje F. Tigchelaar
    • , Cisca Wijmenga
    • , Alexandra Zhernakova
    •  & Pim van der Harst
  16. Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia

    • Silva Kasela
    • , Krista Fischer
    • , Natalia Pervjakova
    •  & Lili Milani
  17. Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia

    • Silva Kasela
    •  & Natalia Pervjakova
  18. MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK

    • Rebecca C. Richmond
    • , Tom R. Gaunt
    • , George Davey Smith
    •  & Caroline L. Relton
  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

    • Marco Adamo
    • , Mohamed Elkalaawy
    • , Majid Hashemi
    • , Andrew Jenkinson
    •  & Rachel L. Batterham
  20. Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland

    • Mika Ala-Korpela
    •  & Pasi Soininen
  21. NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland

    • Mika Ala-Korpela
    •  & Pasi Soininen
  22. Computational Medicine, School of Social and Community Medicine, University of Bristol and Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    • Mika Ala-Korpela
  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

    • Benedetta Albetti
    • , Pier Alberto Bertazzi
    • , Valeria Motta
    • , Federica Rota
    • , Letizia Tarantini
    •  & Valentina Bollati
  24. Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel Campus, Kiel, Germany

    • Ole Ammerpohl
    •  & Reiner Siebert
  25. Centre for Haematology, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, UK

    • Jane F. Apperley
    • , Michael Laffan
    •  & Georgios Nteliopoulos
  26. Molecular Epidemiology, Leiden University Medical Center, Leiden, 2333 ZC, The Netherlands

    • Marian Beekman
    • , P. Eline Slagboom
    •  & Bastiaan T. Heijmans
  27. Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College London, London W12 0NN, UK

    • S. Lucas Black
  28. High Throughput Genomics—Oxford Genomic Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK

    • Christine Blancher
  29. Medical Department 1, University Hospital of the Technical University Dresden, Dresden, Germany

    • Mario Brosch
    •  & Jochen Hampe
  30. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    • Maren Carstensen-Kirberg
    • , Michael Roden
    •  & Christian Herder
  31. Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands

    • Anton J. M. de Craen
  32. Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7PX, UK

    • Simon de Lusignan
  33. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands

    • Abbas Dehghan
    • , Oscar H. Franco
    • , Aaron Isaacs
    • , Cornelia van Duijn
    •  & Albert Hofman
  34. Clinical and Experimental Surgery Department, Medical Research Institute, University of Alexandria, Hadara, Alexandria 21561, Egypt

    • Mohamed Elkalaawy
  35. Department of Endocrinology, Diabetes and Obesity, Max Healthcare, New Delhi 110 017, India

    • Sujeet Jha
  36. Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo 1628655, Japan

    • Norihiro Kato
  37. Epidemiology and Prevention Unit, Fondazione IRCSS Istituto Nazionale Tumori, Milano, Italy

    • Vittorio Krogh
  38. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    • Thomas Meitinger
    • , Holger Prokisch
    •  & Katharina Schramm
  39. Institute of Human Genetics, Technical University Munich, München, Germany

    • Thomas Meitinger
    • , Holger Prokisch
    •  & Katharina Schramm
  40. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

    • Thomas Meitinger
    •  & Annette Peters
  41. Vascular Biology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW3 6LY, UK

    • Zacharoula Nikolakopoulou
  42. Dipartmento Di Medicina Clinica E Chirurgia Federio II University, Naples, Italy

    • Salvatore Panico
  43. Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    • Wolfgang Rathmann
  44. Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Hospital Düsseldorf, Düsseldorf, Germany

    • Michael Roden
  45. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

    • Johanna K. Sandling
    • , Tsun-Po Yang
    •  & Panos Deloukas
  46. Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 751 44 Uppsala, Sweden

    • Johanna K. Sandling
  47. Department of Visceral and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel Campus, Kiel, Germany

    • Clemens Schafmayer
  48. Institute of Human Genetics, University Hospital of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany

    • Reiner Siebert
  49. Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands

    • Lisette Stolk
    •  & Joyce B. J. van Meurs
  50. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany

    • Konstantin Strauch
  51. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore

    • E-Shyong Tai
  52. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore

    • E-Shyong Tai
  53. Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore

    • E-Shyong Tai
  54. Cancer Registry and Histopathology Unit, ‘Civile—M.P. Arezzo’ Hospital, ASP 7, Ragusa, Italy

    • Rosario Tumino
  55. Departments of Internal Medicine and Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands

    • Andre G. Uitterlinden
  56. Epidemiology and Public Health, Imperial College London, London, UK

    • Paolo Vineis
  57. Department of Public Health, Faculty of Medicine, University of Kelaniya, PO Box 6, Thalagolla Road, Ragama 11010, Sri Lanka

    • Ananda Rajitha Wickremasinghe
  58. The Institute of Cancer Research, Surrey SM2 5NG, UK

    • Wei Yuan
  59. Centre for Obesity Research, Rayne Institute, Department of Medicine, University College London, London WC1E 6JJ, UK

    • Rachel L. Batterham
  60. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK

    • Panos Deloukas
  61. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 21589, Saudi Arabia

    • Panos Deloukas
  62. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA

    • Cecilia M. Lindgren
  63. University of Groningen, University Medical Center Groningen, Department of Cardiology, 9700 RB Groningen, The Netherlands

    • Pim van der Harst
  64. Durrer Center for Cardiogenetic Research, ICIN—Netherlands Heart Institute, 3511 GC Utrecht, The Netherlands

    • Pim van der Harst
  65. Hannover Unified Biobank, Hannover Medical School, Feodor-Lynen-Strasse 15, D-30625 Hanover, Germany

    • Thomas Illig
  66. Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hanover, Germany

    • Thomas Illig
  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

    • Marjo-Riitta Järvelin
  68. Biocenter Oulu, P.O. Box 5000, Aapistie 5A, FI-90014 University of Oulu, Finland

    • Marjo-Riitta Järvelin
  69. Center for Life Course Epidemiology, Faculty of Medicine, P.O. Box 5000, FI-90014 University of Oulu, Finland

    • Marjo-Riitta Järvelin
  70. Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, PO Box 20, FI-90220 Oulu, 90029 OYS, Finland

    • Marjo-Riitta Järvelin
  71. Department of Pathology, National University Hospital, Singapore

    • Richie Soong
  72. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK

    • Mark I. McCarthy
  73. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK

    • Mark I. McCarthy
  74. Imperial College Healthcare NHS Trust, London W12 0HS, UK

    • Paul Elliott
    • , Jaspal S. Kooner
    •  & John C. Chambers
  75. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

    • John C. Chambers

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Data collection and analysis in the contributing population studies, ALSPAC study: T.R.G., C.L.R., R.C.R., G.D.S.; EGCUT study: K.F., S.Ka., L.M., N.P.; EPICOR study: G.F., S.G., V.K., G.M., S.P., R.T., P.V.; KORA study: M.C.K., C.G., H.G., C.H., T.I., J.K., S.Ku., C.M., T.M., A.P., H.P., J.S.R., M.R., W.R., K.Sc., K.St., B.T., M.W., S.W.; Leiden Longevity Study: M.B., A.J.M.d.C., B.T.H., P.E.S.; LIFELINES study: M.J.B., L.F., P.v.d.H., E.F.T., C.W., A.Z.; LOLIPOP study: B.A., U.A., C.B, P.A.B., V.B., J.C.C., A.Dr., P.E., M.R.J., S.J., J.S.K., M.A.K., N.K., B.L., C.M.L., M.Lo., S.d.L., M.I.M., V.M., Z.Y.M., H.K.N., F.R., M.A.R., J.S., P.S., R.So., W.R.S., E.S.T., L.T., S.T., A.R.W., W.Z.; Rotterdam Study: A.De., C.v.D., O.H.F., A.H., A.I., J.B.J.v.M., L.S., A.G.U.; TwinsUK study: J.T.B., P.D., J.K.S., T.D.S., P.C.T., T.P.Y., WY. Data collection and molecular analyses in isolated cell subsets; adipocytes: M.A., R.L.B., J.C.C., M.E., M.H., A.J., J.S.K., Z.Y.M., H.K.N., M.A.R., J.S., R.So., W.R.S., S.T.; hepatocytes: O.A., M.Br., J.H., C.S., R.Si.; leucocytes: J.F.A., S.L.B., J.C.C., J.S.K., M.La., Z.Y.M., H.K.N., G.N., Z.N., M.A.R., R.So., W.R.S., S.T., Y.Y. Data analysis and writing group; J.C.C., A.Dr., P.E., J.S.K., C.G., H.G., B.L., M.Lo., G.M., M.I.M., J.S., W.R.S., S.W.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jaspal S. Kooner or Harald Grallert or John C. Chambers.

Reviewer Information Nature thanks M. Boehnke, J. M. Greally, B. Voight and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Tables

    This file contains Supplementary Tables 1-30 (see Supplementary Information file for legends).

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https://doi.org/10.1038/nature20784

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