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

Nature Genetics volume 41, pages 25–34 (2009)Cite this article

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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Figure 1: Genome-wide association results for GIANT (stage 1).
Figure 2: Regional association plots showing signals in stage 1 samples for replicating loci around TMEM18, GNPDA2, SH2B1, MTCH2, KCTD15 and NEGR1.
Figure 3: Combined impact of risk alleles on average BMI in the population-based EPIC-Norfolk cohort.
Figure 4: Contribution of copy number polymorphism to BMI.

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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

  1. A full list of members is provided in the Supplementary Note online.

  2. Cristen J Willer, Elizabeth K Speliotes, Ruth J F Loos and Shengxu Li: These authors contributed equally to this work.

  3. 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 and Joel N Hirschhorn: Members of the writing team.

  4. Mark I McCarthy, Michael Boehnke, Inês Barroso, Gonçalo R Abecasis and Joel N Hirschhorn: These authors jointly directed the project.

Authors and Affiliations

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

    Cristen J Willer, Anne U Jackson, Laura J Scott, Heather M Stringham & Michael Boehnke

  2. Division of Gastroenterology, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Elizabeth K Speliotes

  3. Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, 02142, Massachusetts, 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, Neuherberg, 85764, Germany

    Iris M Heid, Claudia Lamina, Christian Gieger & H-Erich Wichmann

  8. Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Sonja I Berndt, Stephen J Chanock & Richard B Hayes

  9. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, 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, 02144, Massachusetts, USA

    Amanda L Elliott, Steven A McCarroll & David Altshuler

  11. Program in Genomics and Divisions of Endocrinology and Genetics, Children's Hospital, Boston, 02115, Massachusetts, USA

    Guillaume Lettre, Helen N Lyon & Joel N Hirschhorn

  12. Medical Genetics/Clinical Pharmacology and Discovery Medicine, King of Prussia, 19406, Pennsylvania, 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, 02115, Massachusetts, USA

    Lu Qi, Frank B Hu & David J Hunter

  15. Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, 02115, Massachusetts, 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. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, Michigan, 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, Rotterdam, NL-3000-CA, 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, 21225, Maryland, USA

    Toshiko Tanaka & Luigi Ferrucci

  24. Department of Social Medicine, MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, BS8 2PR, UK

    Nicholas J Timpson, George Davey Smith & David M Evans

  25. Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Malmö, 20502, Sweden

    Peter Almgren & Leif C Groop

  26. DRL, OCDEM, Churchill Hospital, Headington, OX3 7LJ, Oxford, UK

    Amanda Bennett

  27. Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, 90033, California, 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, 20892, Maryland, USA

    Lori L Bonnycastle, Peter Chines, Francis S Collins, Parimal Deodhar, Michael R Erdos, Narisu Narisu & Matthew G Rees

  31. Cambridge, Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, 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, Helsinki, FI-00300, Finland

    Aki S Havulinna, Pekka Jousilahti & Veikko Salomaa

  37. Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Virchowstr. 174, Essen, 45147, Germany

    Johannes Hebebrand

  38. Department of Epidemiology, Erasmus MC, PO Box 2400, Rotterdam, NL-3000-CA, 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, Jakobstad, FIN-00014, Finland

    Bo Isomaa

  40. Bioinformed Consulting Services, Gaithersburg, 20877, Maryland, USA

    Kevin B Jacobs

  41. Department of Medical Genetics, University of Lausanne, Lausanne, CH-1005, Switzerland

    Toby Johnson

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

    Toby Johnson

  43. Swiss Institute of Bioinformatics, Lausanne, CH-1005, 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, 02115, Massachusetts, USA

    Peter Kraft & David J Hunter

  47. Department of Molecular Medicine, National Public Health Institute, Helsinki, FIN-00300, Finland

    Mikko Kuokkanen & Kaisa Silander

  48. Department of Medicine, University of Kuopio, Kuopio, 70210, Finland

    Johanna Kuusisto & Markku Laakso

  49. Finnish Institute of Occupational Health, Aapistie 1, Oulu, Fin-90220, Finland

    Jaana Laitinen

  50. Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, 21224, Maryland, 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. Department of Social Medicine, Avon Longitudinal Study of Parents and Children (ALSPAC), 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, Neuherberg, 85764, Germany

    Thomas Meitinger

  54. Institute of Human Genetics, Technical University Munich, Munich, D-81765, 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, Malmö, 20502, Sweden

    Martin Ridderstråle

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

    Aimo Ruokonen

  59. Savitaipale Health Center, Savitaipale, FIN-54800, 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. Department of Epidemiology and Health Promotion, National Public Health Institute, Mannerheimintie 166, Helsinki, FIN-00300, Finland

    Timo T Valle & Jaakko Tuomilehto

  63. Department of Internal Medicine, BH-10 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011, Switzerland

    Peter Vollenweider & Gerard Waeber

  64. Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, CHP-220, 90089, California, USA

    Richard M Watanabe

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

    Jack M Guralnik

  66. Peninsula Medical School, Exeter, EX5 2DW, UK

    Andrew T Hattersley

  67. Department of Medicine, Helsinki University Central Hospital, Helsinki, FIN-00290, Finland

    Tiinamaija Tuomi

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

    Tiinamaija Tuomi

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

    Leif C Groop

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

    Karen L Mohlke

  71. Institute of Molecular Medicine, University of Helsinki, Helsinki, FIN-00014, Finland

    Leena Peltonen

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

    David Schlessinger

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

    H-Erich Wichmann

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

    Mark I McCarthy

  75. Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Joel N Hirschhorn

Consortia

the GIANT Consortium

  • Cristen J Willer
  • , Elizabeth K Speliotes
  • , Ruth J F Loos
  • , Shengxu Li
  • , Cecilia M Lindgren
  • , Iris M Heid
  • , Sonja I Berndt
  • , Amanda L Elliott
  • , Anne U Jackson
  • , Claudia Lamina
  • , Guillaume Lettre
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  • , Konstantinos Papadakis
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  • , Rosa Maria Roccasecca
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  • , Inga Prokopenko
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  • , Nicholas J Timpson
  • , Peter Almgren
  • , Amanda Bennett
  • , Richard N Bergman
  • , Sheila A Bingham
  • , Lori L Bonnycastle
  • , Morris Brown
  • , Noël P Burtt
  • , Peter Chines
  • , Lachlan Coin
  • , Francis S Collins
  • , John M Connell
  • , Cyrus Cooper
  • , George Davey Smith
  • , Elaine M Dennison
  • , Parimal Deodhar
  • , Paul Elliott
  • , Michael R Erdos
  • , Karol Estrada
  • , David M Evans
  • , Lauren Gianniny
  • , Christian Gieger
  • , Christopher J Gillson
  • , Candace Guiducci
  • , Rachel Hackett
  • , David Hadley
  • , Alistair S Hall
  • , Aki S Havulinna
  • , Johannes Hebebrand
  • , Albert Hofman
  • , Bo Isomaa
  • , Kevin B Jacobs
  • , Toby Johnson
  • , Pekka Jousilahti
  • , Zorica Jovanovic
  • , Kay-Tee Khaw
  • , Peter Kraft
  • , Mikko Kuokkanen
  • , Johanna Kuusisto
  • , Jaana Laitinen
  • , Edward G Lakatta
  • , Jian'an Luan
  • , Robert N Luben
  • , Massimo Mangino
  • , Wendy L McArdle
  • , Thomas Meitinger
  • , Antonella Mulas
  • , Patricia B Munroe
  • , Narisu Narisu
  • , Andrew R Ness
  • , Kate Northstone
  • , Stephen O'Rahilly
  • , Carolin Purmann
  • , Matthew G Rees
  • , Martin Ridderstråle
  • , Susan M Ring
  • , Fernando Rivadeneira
  • , Aimo Ruokonen
  • , Manjinder S Sandhu
  • , Jouko Saramies
  • , Laura J Scott
  • , Angelo Scuteri
  • , Kaisa Silander
  • , Matthew A Sims
  • , Kijoung Song
  • , Jonathan Stephens
  • , Suzanne Stevens
  • , Heather M Stringham
  • , Y C Loraine Tung
  • , Timo T Valle
  • , Cornelia M Van Duijn
  • , Karani S Vimaleswaran
  • , Peter Vollenweider
  • , Gerard Waeber
  • , Chris Wallace
  • , Richard M Watanabe
  • , Dawn M Waterworth
  • , Nicholas Watkins
  • , Jacqueline C M Witteman
  • , Eleftheria Zeggini
  • , Guangju Zhai
  • , M Carola Zillikens
  • , David Altshuler
  • , Mark J Caulfield
  • , Stephen J Chanock
  • , I Sadaf Farooqi
  • , Luigi Ferrucci
  • , Jack M Guralnik
  • , Andrew T Hattersley
  • , Frank B Hu
  • , Marjo-Riitta Jarvelin
  • , Markku Laakso
  • , Vincent Mooser
  • , Ken K Ong
  • , Willem H Ouwehand
  • , Veikko Salomaa
  • , Nilesh J Samani
  • , Timothy D Spector
  • , Tiinamaija Tuomi
  • , Jaakko Tuomilehto
  • , Manuela Uda
  • , André G Uitterlinden
  • , Nicholas J Wareham
  • , Panagiotis Deloukas
  • , Timothy M Frayling
  • , Leif C Groop
  • , Richard B Hayes
  • , David J Hunter
  • , Karen L Mohlke
  • , Leena Peltonen
  • , David Schlessinger
  • , David P Strachan
  • , H-Erich Wichmann
  • , Mark I McCarthy
  • , Michael Boehnke
  • , Inês Barroso
  • , Gonçalo R Abecasis
  •  & Joel N Hirschhorn

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.

Corresponding authors

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

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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).

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Tables 1–9 and Supplementary Note (PDF 1940 kb)

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the GIANT Consortium. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41, 25–34 (2009). https://doi.org/10.1038/ng.287

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