Article abstract


Nature Genetics 41, 25 - 34 (2008)
Published online: 14 December 2008 | doi:10.1038/ng.287

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

Cristen J Willer1,77,78, Elizabeth K Speliotes2,3,77,78, Ruth J F Loos4,5,77,78, Shengxu Li4,5,77,78, Cecilia M Lindgren6,78, Iris M Heid7,78, Sonja I Berndt8, Amanda L Elliott9,10, Anne U Jackson1, Claudia Lamina7, Guillaume Lettre9,11, Noha Lim12, Helen N Lyon3,11, Steven A McCarroll9,10, Konstantinos Papadakis13, Lu Qi14,15, Joshua C Randall6, Rosa Maria Roccasecca16, Serena Sanna17, Paul Scheet18, Michael N Weedon19, Eleanor Wheeler16, Jing Hua Zhao4,5, Leonie C Jacobs20, Inga Prokopenko6,21, Nicole Soranzo16,22, Toshiko Tanaka23, Nicholas J Timpson24, Peter Almgren25, Amanda Bennett26, Richard N Bergman27, Sheila A Bingham28,29, Lori L Bonnycastle30, Morris Brown31, Noël P Burtt9, Peter Chines30, Lachlan Coin32, Francis S Collins30, John M Connell33, Cyrus Cooper34, George Davey Smith24, Elaine M Dennison34, Parimal Deodhar30, Paul Elliott32, Michael R Erdos30, Karol Estrada20, David M Evans24, Lauren Gianniny9, Christian Gieger7, Christopher J Gillson4,5, Candace Guiducci9, Rachel Hackett9, David Hadley13, Alistair S Hall35, Aki S Havulinna36, Johannes Hebebrand37, Albert Hofman38, Bo Isomaa39, Kevin B Jacobs40, Toby Johnson41,42,43, Pekka Jousilahti36, Zorica Jovanovic5,44, Kay-Tee Khaw45, Peter Kraft46, Mikko Kuokkanen9,47, Johanna Kuusisto48, Jaana Laitinen49, Edward G Lakatta50, Jian'an Luan4,5, Robert N Luben45, Massimo Mangino51, Wendy L McArdle52, Thomas Meitinger53,54, Antonella Mulas17, Patricia B Munroe55, Narisu Narisu30, Andrew R Ness56, Kate Northstone52, Stephen O'Rahilly5,44, Carolin Purmann5,44, Matthew G Rees30, Martin Ridderstråle57, Susan M Ring52, Fernando Rivadeneira20,38, Aimo Ruokonen58, Manjinder S Sandhu4,45, Jouko Saramies59, Laura J Scott1, Angelo Scuteri60, Kaisa Silander47, Matthew A Sims4,5, Kijoung Song12, Jonathan Stephens61, Suzanne Stevens51, Heather M Stringham1, Y C Loraine Tung5,44, Timo T Valle62, Cornelia M Van Duijn38, Karani S Vimaleswaran4,5, Peter Vollenweider63, Gerard Waeber63, Chris Wallace55, Richard M Watanabe64, Dawn M Waterworth12, Nicholas Watkins61, Jacqueline C M Witteman38, Eleftheria Zeggini6, Guangju Zhai22, M Carola Zillikens20, David Altshuler9,10, Mark J Caulfield55, Stephen J Chanock8, I Sadaf Farooqi5,44, Luigi Ferrucci23, Jack M Guralnik65, Andrew T Hattersley66, Frank B Hu14,15, Marjo-Riitta Jarvelin32, Markku Laakso48, Vincent Mooser12, Ken K Ong4,5, Willem H Ouwehand16,61, Veikko Salomaa36, Nilesh J Samani51, Timothy D Spector22, Tiinamaija Tuomi67,68, Jaakko Tuomilehto62, Manuela Uda17, André G Uitterlinden20,38, Nicholas J Wareham4,5, Panagiotis Deloukas16, Timothy M Frayling19, Leif C Groop25,69, Richard B Hayes8, David J Hunter9,14,15,46, Karen L Mohlke70, Leena Peltonen9,16,71, David Schlessinger72, David P Strachan13, H-Erich Wichmann7,73, Mark I McCarthy6,21,74,78,79, Michael Boehnke1,78,79, Inês Barroso16,78,79, Gonçalo R Abecasis18,78,79 & Joel N Hirschhorn3,11,75,78,79 for the GIANT Consortium80


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 times 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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  1. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA.
  2. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  3. Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts 02142, USA.
  4. Medical Research Council Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  5. Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  6. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  7. Institute of Epidemiology, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
  8. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
  9. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
  10. Department of Molecular Biology, Massachusetts General Hospital, Cambridge, Massachusetts 02144, USA.
  11. Program in Genomics and Divisions of Endocrinology and Genetics, Children's Hospital, Boston, Massachusetts 02115, USA.
  12. Medical Genetics/Clinical Pharmacology and Discovery Medicine, King of Prussia, Pennsylvania 19406, USA.
  13. Division of Community Health Sciences, St. George's, University of London, London SW17 0RE, UK.
  14. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
  15. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
  16. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  17. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari 09042, Italy.
  18. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  19. Genetics of Complex Traits, Peninsula Medical School, Exeter EX1 2LU, UK.
  20. Department of Internal Medicine, Erasmus MC, PO Box 2400, NL-3000-CA Rotterdam, The Netherlands.
  21. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
  22. Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
  23. National Institute of Aging, Clinical Research Branch - Longitudinal Studies Section, Baltimore, Maryland 21225, USA.
  24. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol BS8 2PR, UK.
  25. Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden.
  26. DRL, OCDEM, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
  27. Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California 90033, USA.
  28. MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
  29. MRC Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Cambridge CB1 8RN, UK.
  30. National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
  31. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  32. Department of Epidemiology and Public Health, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, UK.
  33. British Heart Foundation Glasgow Cardiovascular Research Centre, Faculty of Medicine, University of Glasgow, Glasgow G12 8TA, UK.
  34. MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
  35. Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, UK.
  36. KTL-National Public Health Institute, FI-00300 Helsinki, Finland.
  37. Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Virchowstr. 174, 45147 Essen, Germany.
  38. Department of Epidemiology, Erasmus MC, PO Box 2400, NL-3000-CA Rotterdam, The Netherlands.
  39. Folkhalsan Research Center, Malmska Municipal Health Center and Hospital, FIN-00014 Jakobstad, Finland.
  40. Bioinformed Consulting Services, Gaithersburg, Maryland 20877, USA.
  41. Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland.
  42. University Institute for Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), CH-1005 Lausanne, Switzerland.
  43. Swiss Institute of Bioinformatics, CH-1005 Lausanne, Switzerland.
  44. University of Cambridge Metabolic Research Laboratories, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  45. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 0SR, UK.
  46. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
  47. Department of Molecular Medicine, National Public Health Institute, FIN-00300 Helsinki, Finland.
  48. Department of Medicine, University of Kuopio, 70210 Kuopio, Finland.
  49. Finnish Institute of Occupational Health, Aapistie 1, Fin-90220 Oulu, Finland.
  50. Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
  51. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences, Glenfield General Hospital, Leicester LE3 9QP, UK.
  52. Avon Longitudinal Study of Parents and Children (ALSPAC), Department of Social Medicine, University of Bristol, Bristol BS8 1TQ, UK.
  53. Institute of Human Genetics, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
  54. Institute of Human Genetics, Technical University Munich, D-81765, Munich, Germany.
  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.
  56. Department of Oral & Dental Science, University of Bristol, Bristol BS1 2LY, UK.
  57. Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden.
  58. Department of Clinical Chemistry, University of Oulu, Fin-90220 Oulu, Finland.
  59. Savitaipale Health Center, FIN-54800 Savitaipale, Finland.
  60. Unitá Operativa Geriatria, Istituto Nazionale Ricovero e Cura Anziani, Rome 00189, Italy.
  61. Department of Haematology, University of Cambridge/NHS Blood & Transplant, Cambridge CB2 2PR, UK.
  62. National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, FIN-00300, Helsinki, Finland.
  63. Department of Internal Medicine, BH-10 Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland.
  64. Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, CHP-220, Los Angeles, California 90089, USA.
  65. Laboratory of Epidemiology, Demography, and Biometry; Gerontology Research Center, National Institute on Aging, Bethesda, Maryland, 20892, USA.
  66. Peninsula Medical School, Exeter EX5 2DW, UK.
  67. Department of Medicine, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland.
  68. Research Program of Molecular Medicine, University of Helsinki, FIN-00014 Helsinki, Finland.
  69. Department of Medicine, Helsinki University, FIN-00029 Helsinki, Finland.
  70. Department of Genetics, University of North Carolina, CB #7264, Chapel Hill, North Carolina 27599, USA.
  71. Institute of Molecular Medicine, University of Helsinki, FIN-00014 Helsinki, Finland.
  72. Laboratory of Genetics, US National Institutes of Health Biomedical Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
  73. Institute of Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University München, Marchioninistr. 15, 81377 München, Germany.
  74. National Institute for Health Research, Oxford Biomedical Research Centre, University of Oxford, Old Road, Headington, Oxford OX3 7LJ, UK.
  75. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  76. A full list of members is provided in the Supplementary Note online.
  77. These authors contributed equally to this work.
  78. Members of the writing team.
  79. These authors jointly directed the project.
  80. All authors are members of the Genetic Investigation of ANthropometric Traits (GIANT) Consortium.

Correspondence to: e-mail: joelh@broad.mit.edu

Correspondence to: e-mail: goncalo@umich.edu

Correspondence to: e-mail: ib1@sanger.ac.uk

Correspondence to: e-mail: boehnke@umich.edu

Correspondence to: e-mail: mark.mccarthy@drl.ox.ac.uk



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