Article | Published:

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Nature Genetics volume 41, pages 2534 (2009) | Download Citation

Abstract

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

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Acknowledgements

We are extremely grateful to all of the participants in each of the studies contributing to this effort. Full acknowledgments can be found in the Supplementary Note.

Support for this research was provided by: US National Institutes of Health grants CA65725, CA87969, CA49449, CA67262, CA50385, DK062370, DK072193, DK075787, HG02651, HL084729, HL087679 (through STAMPEED, 1RL1MH083268), 5UO1CA098233, 1Z01 HG000024, 1RL1MH083268, T32 DK07191, F32 DK079466, K23 DK080145, K23 DK067288, CIDR NIH Contract Number N01-HG-65403, NIA contract NO1-AG-1-2109; the Intramural Research Program of the Division of Cancer Epidemiology and Genetics; contracts from the Division of Cancer Prevention, National Cancer Institute and EU FP6 funding (contract no LSHM-CT-2003-503041); GlaxoSmithKline; the Faculty of Biology and Medicine of Lausanne, Switzerland; the Intramural Research Program of the National Institute on Aging (NIA); Cancer Research United Kingdom; the UK Medical Research Council (including grants G0000649, G0000934 and G0601261); the Wellcome Trust (including Strategic Award 076113, grants 068545/Z/02 and 076467/Z/05/Z); the NIHR through the Biomedical Research Centres at Oxford, King's College London; Guys and St. Thomas' Foundation Hospitals' Trust; the British Heart Foundation (including grant FS/05/061/19501), European Community's Seventh Framework Programme (ENGAGE:HEALTH-F4-2007-201413); Diabetes UK; Unilever Corporate Research; American Diabetes Association including a Smith Family Foundation Pinnacle Program Project Award #7-03-PPG-04R; the Academy of Finland (grants 118065 and 124243); National Genome Research Net Germany; Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; the Helmholtz Center Munich; the Sigrid Juselius Foundation; University of Bristol; Linné grant from Swedish Research Council; Wallenberg Foundation; Folkhälsan Research Foundation; University of Southampton; Netherlands Organisation of Scientific Research NWO (nr. 175.010.2005.011); Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry for Health, Welfare and Sports; the European Commision (DG XII) and the Municipality of Rotterdam. G.R.A. and K.L.M. are Pew Scholars for the Biomedical Sciences; A.L.E. is supported by a Sarnoff Cardiovascular Research Foundation Fellowship; C.M.L. is a Nuffield Department of Medicine Scientific Leadership Fellow; S.A.M. is supported by a Life Sciences Research Fellowship; M.K. is supported by the Finnish Cultural Foundation; N.J.S. holds a BHF Chair; M.N.W. is a Vandervell Foundation Research Fellow; C.J.W. is supported by an American Diabetes Association postdoctoral fellowship; and E.Z. is a Wellcome Trust-RD Fellow (grant number 079557).

Author information

Author notes

    • Cristen J Willer
    • , Elizabeth K Speliotes
    • , Ruth J F Loos
    •  & Shengxu Li

    These authors contributed equally to this work.

    • Cristen J Willer
    • , Elizabeth K Speliotes
    • , Ruth J F Loos
    • , Shengxu Li
    • , Cecilia M Lindgren
    • , Iris M Heid
    • , Mark I McCarthy
    • , Michael Boehnke
    • , Inês Barroso
    • , Gonçalo R Abecasis
    •  & Joel N Hirschhorn

    Members of the writing team.

    • Mark I McCarthy
    • , Michael Boehnke
    • , Inês Barroso
    • , Gonçalo R Abecasis
    •  & Joel N Hirschhorn

    These authors jointly directed the project.

Affiliations

  1. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Cristen J Willer
    • , Anne U Jackson
    • , Laura J Scott
    • , Heather M Stringham
    •  & Michael Boehnke
  2. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Elizabeth K Speliotes
  3. Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts 02142, USA.

    • Elizabeth K Speliotes
    • , Helen N Lyon
    •  & Joel N Hirschhorn
  4. Medical Research Council Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

    • Ruth J F Loos
    • , Shengxu Li
    • , Jing Hua Zhao
    • , Christopher J Gillson
    • , Jian'an Luan
    • , Manjinder S Sandhu
    • , Matthew A Sims
    • , Karani S Vimaleswaran
    • , Ken K Ong
    •  & Nicholas J Wareham
  5. Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

    • Ruth J F Loos
    • , Shengxu Li
    • , Jing Hua Zhao
    • , Christopher J Gillson
    • , Zorica Jovanovic
    • , Jian'an Luan
    • , Stephen O'Rahilly
    • , Carolin Purmann
    • , Matthew A Sims
    • , Y C Loraine Tung
    • , Karani S Vimaleswaran
    • , I Sadaf Farooqi
    • , Ken K Ong
    •  & Nicholas J Wareham
  6. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

    • Cecilia M Lindgren
    • , Joshua C Randall
    • , Inga Prokopenko
    • , Eleftheria Zeggini
    •  & Mark I McCarthy
  7. Institute of Epidemiology, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.

    • Iris M Heid
    • , Claudia Lamina
    • , Christian Gieger
    •  & H-Erich Wichmann
  8. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.

    • Sonja I Berndt
    • , Stephen J Chanock
    •  & Richard B Hayes
  9. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Amanda L Elliott
    • , Guillaume Lettre
    • , Steven A McCarroll
    • , Noël P Burtt
    • , Lauren Gianniny
    • , Candace Guiducci
    • , Rachel Hackett
    • , Mikko Kuokkanen
    • , David Altshuler
    • , David J Hunter
    •  & Leena Peltonen
  10. Department of Molecular Biology, Massachusetts General Hospital, Cambridge, Massachusetts 02144, USA.

    • Amanda L Elliott
    • , Steven A McCarroll
    •  & David Altshuler
  11. Program in Genomics and Divisions of Endocrinology and Genetics, Children's Hospital, Boston, Massachusetts 02115, USA.

    • Guillaume Lettre
    • , Helen N Lyon
    •  & Joel N Hirschhorn
  12. Medical Genetics/Clinical Pharmacology and Discovery Medicine, King of Prussia, Pennsylvania 19406, USA.

    • Noha Lim
    • , Kijoung Song
    • , Dawn M Waterworth
    •  & Vincent Mooser
  13. Division of Community Health Sciences, St. George's, University of London, London SW17 0RE, UK.

    • Konstantinos Papadakis
    • , David Hadley
    •  & David P Strachan
  14. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Lu Qi
    • , Frank B Hu
    •  & David J Hunter
  15. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

    • Lu Qi
    • , Frank B Hu
    •  & David J Hunter
  16. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

    • Rosa Maria Roccasecca
    • , Eleanor Wheeler
    • , Nicole Soranzo
    • , Willem H Ouwehand
    • , Panagiotis Deloukas
    • , Leena Peltonen
    •  & Inês Barroso
  17. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari 09042, Italy.

    • Serena Sanna
    • , Antonella Mulas
    •  & Manuela Uda
  18. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Paul Scheet
    •  & Gonçalo R Abecasis
  19. Genetics of Complex Traits, Peninsula Medical School, Exeter EX1 2LU, UK.

    • Michael N Weedon
    •  & Timothy M Frayling
  20. Department of Internal Medicine, Erasmus MC, PO Box 2400, NL-3000-CA Rotterdam, The Netherlands.

    • Leonie C Jacobs
    • , Karol Estrada
    • , Fernando Rivadeneira
    • , M Carola Zillikens
    •  & André G Uitterlinden
  21. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Inga Prokopenko
    •  & Mark I McCarthy
  22. Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.

    • Nicole Soranzo
    • , Guangju Zhai
    •  & Timothy D Spector
  23. National Institute of Aging, Clinical Research Branch - Longitudinal Studies Section, Baltimore, Maryland 21225, USA.

    • Toshiko Tanaka
    •  & Luigi Ferrucci
  24. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol BS8 2PR, UK.

    • Nicholas J Timpson
    • , George Davey Smith
    •  & David M Evans
  25. Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden.

    • Peter Almgren
    •  & Leif C Groop
  26. DRL, OCDEM, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.

    • Amanda Bennett
  27. Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California 90033, USA.

    • Richard N Bergman
  28. MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.

    • Sheila A Bingham
  29. MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Cambridge CB1 8RN, UK.

    • Sheila A Bingham
  30. National Human Genome Research Institute, Bethesda, Maryland 20892, USA.

    • Lori L Bonnycastle
    • , Peter Chines
    • , Francis S Collins
    • , Parimal Deodhar
    • , Michael R Erdos
    • , Narisu Narisu
    •  & Matthew G Rees
  31. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

    • Morris Brown
  32. Department of Epidemiology and Public Health, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, UK.

    • Lachlan Coin
    • , Paul Elliott
    •  & Marjo-Riitta Jarvelin
  33. British Heart Foundation Glasgow Cardiovascular Research Centre, Faculty of Medicine, University of Glasgow, Glasgow G12 8TA, UK.

    • John M Connell
  34. MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.

    • Cyrus Cooper
    •  & Elaine M Dennison
  35. Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, UK.

    • Alistair S Hall
  36. KTL-National Public Health Institute, FI-00300 Helsinki, Finland.

    • Aki S Havulinna
    • , Pekka Jousilahti
    •  & Veikko Salomaa
  37. Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Virchowstr. 174, 45147 Essen, Germany.

    • Johannes Hebebrand
  38. Department of Epidemiology, Erasmus MC, PO Box 2400, NL-3000-CA Rotterdam, The Netherlands.

    • Albert Hofman
    • , Fernando Rivadeneira
    • , Cornelia M Van Duijn
    • , Jacqueline C M Witteman
    •  & André G Uitterlinden
  39. Folkhalsan Research Center, Malmska Municipal Health Center and Hospital, FIN-00014 Jakobstad, Finland.

    • Bo Isomaa
  40. Bioinformed Consulting Services, Gaithersburg, Maryland 20877, USA.

    • Kevin B Jacobs
  41. Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland.

    • Toby Johnson
  42. University Institute for Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), CH-1005 Lausanne, Switzerland.

    • Toby Johnson
  43. Swiss Institute of Bioinformatics, CH-1005 Lausanne, Switzerland.

    • Toby Johnson
  44. University of Cambridge Metabolic Research Laboratories, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

    • Zorica Jovanovic
    • , Stephen O'Rahilly
    • , Carolin Purmann
    • , Y C Loraine Tung
    •  & I Sadaf Farooqi
  45. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 0SR, UK.

    • Kay-Tee Khaw
    • , Robert N Luben
    •  & Manjinder S Sandhu
  46. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Peter Kraft
    •  & David J Hunter
  47. Department of Molecular Medicine, National Public Health Institute, FIN-00300 Helsinki, Finland.

    • Mikko Kuokkanen
    •  & Kaisa Silander
  48. Department of Medicine, University of Kuopio, 70210 Kuopio, Finland.

    • Johanna Kuusisto
    •  & Markku Laakso
  49. Finnish Institute of Occupational Health, Aapistie 1, Fin-90220 Oulu, Finland.

    • Jaana Laitinen
  50. Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.

    • Edward G Lakatta
  51. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences, Glenfield General Hospital, Leicester LE3 9QP, UK.

    • Massimo Mangino
    • , Suzanne Stevens
    •  & Nilesh J Samani
  52. Avon Longitudinal Study of Parents and Children (ALSPAC), Department of Social Medicine, University of Bristol, Bristol BS8 1TQ, UK.

    • Wendy L McArdle
    • , Kate Northstone
    •  & Susan M Ring
  53. Institute of Human Genetics, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.

    • Thomas Meitinger
  54. Institute of Human Genetics, Technical University Munich, D-81765, Munich, Germany.

    • Thomas Meitinger
  55. Clinical Pharmacology, The William Harvey Research Institute, Bart's and The London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.

    • Patricia B Munroe
    • , Chris Wallace
    •  & Mark J Caulfield
  56. Department of Oral & Dental Science, University of Bristol, Bristol BS1 2LY, UK.

    • Andrew R Ness
  57. Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden.

    • Martin Ridderstråle
  58. Department of Clinical Chemistry, University of Oulu, Fin-90220 Oulu, Finland.

    • Aimo Ruokonen
  59. Savitaipale Health Center, FIN-54800 Savitaipale, Finland.

    • Jouko Saramies
  60. Unitá Operativa Geriatria, Istituto Nazionale Ricovero e Cura Anziani, Rome 00189, Italy.

    • Angelo Scuteri
  61. Department of Haematology, University of Cambridge/NHS Blood & Transplant, Cambridge CB2 2PR, UK.

    • Jonathan Stephens
    • , Nicholas Watkins
    •  & Willem H Ouwehand
  62. National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, FIN-00300, Helsinki, Finland.

    • Timo T Valle
    •  & Jaakko Tuomilehto
  63. Department of Internal Medicine, BH-10 Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland.

    • Peter Vollenweider
    •  & Gerard Waeber
  64. Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, CHP-220, Los Angeles, California 90089, USA.

    • Richard M Watanabe
  65. Laboratory of Epidemiology, Demography, and Biometry; Gerontology Research Center, National Institute on Aging, Bethesda, Maryland, 20892, USA.

    • Jack M Guralnik
  66. Peninsula Medical School, Exeter EX5 2DW, UK.

    • Andrew T Hattersley
  67. Department of Medicine, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland.

    • Tiinamaija Tuomi
  68. Research Program of Molecular Medicine, University of Helsinki, FIN-00014 Helsinki, Finland.

    • Tiinamaija Tuomi
  69. Department of Medicine, Helsinki University, FIN-00029 Helsinki, Finland.

    • Leif C Groop
  70. Department of Genetics, University of North Carolina, CB #7264, Chapel Hill, North Carolina 27599, USA.

    • Karen L Mohlke
  71. Institute of Molecular Medicine, University of Helsinki, FIN-00014 Helsinki, Finland.

    • Leena Peltonen
  72. Laboratory of Genetics, US National Institutes of Health Biomedical Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.

    • David Schlessinger
  73. Institute of Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University München, Marchioninistr. 15, 81377 München, Germany.

    • H-Erich Wichmann
  74. National Institute for Health Research, Oxford Biomedical Research Centre, University of Oxford, Old Road, Headington, Oxford OX3 7LJ, UK.

    • Mark I McCarthy
  75. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Joel N Hirschhorn

Consortia

  1. the GIANT Consortium

Authors

    Contributions

    The writing team consisted of G.R.A., I.B., M.B., I.M.H., J.N.H., S.L., C.M.L., R.J.F.L., M.I.McC., E.K.S. and C.J.W. Full author contributions and roles are listed in the Supplementary Note.

    Competing interests

    Peter Vollenweider and Gérard Waeber received financial support from GlaxoSmithKline to build the CoLaus study; Dawn Waterworth, Kijoung Song, Noha Lim and Vincent Mooser are full-time employees of GlaxoSmithKline (GSK); Inês Barroso owns stock in the companies GlaxoSmithKline (CSK) and Incyte (INCY).

    Corresponding authors

    Correspondence to Mark I McCarthy or Michael Boehnke or Inês Barroso or Gonçalo R Abecasis or Joel N Hirschhorn.

    Supplementary information

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      Supplementary Text and Figures

      Supplementary Figures 1–5, Supplementary Tables 1–9 and Supplementary Note

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    DOI

    https://doi.org/10.1038/ng.287

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