Letter abstract


Nature Genetics 40, 768 - 775 (2008)
Published online: 4 May 2008 | doi:10.1038/ng.140

Common variants near MC4R are associated with fat mass, weight and risk of obesity

Ruth J F Loos1,2,73, Cecilia M Lindgren3,4,73, Shengxu Li1,2,73, Eleanor Wheeler5, Jing Hua Zhao1,2, Inga Prokopenko3,4, Michael Inouye5, Rachel M Freathy6,7, Antony P Attwood5,8, Jacques S Beckmann9,10, Sonja I Berndt11, The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial71, Sven Bergmann9,12, Amanda J Bennett3,4, Sheila A Bingham13, Murielle Bochud14, Morris Brown15, Stéphane Cauchi16, John M Connell17, Cyrus Cooper18, George Davey Smith19, Ian Day18, Christian Dina16, Subhajyoti De20, Emmanouil T Dermitzakis5, Alex S F Doney21, Katherine S Elliott3, Paul Elliott22,23, David M Evans3,19, I Sadaf Farooqi2,24, Philippe Froguel16,25, Jilur Ghori5, Christopher J Groves3,4, Rhian Gwilliam5, David Hadley26, Alistair S Hall27, Andrew T Hattersley6,7, Johannes Hebebrand28, Iris M Heid29,30, KORA71, Blanca Herrera3,4, Anke Hinney28, Sarah E Hunt5, Marjo-Riitta Jarvelin22,23,31, Toby Johnson9,12,14, Jennifer D M Jolley8, Fredrik Karpe4, Andrew Keniry5, Kay-Tee Khaw32, Robert N Luben32, Massimo Mangino33, Jonathan Marchini34, Wendy L McArdle35, Ralph McGinnis5, David Meyre16, Patricia B Munroe36, Andrew D Morris21, Andrew R Ness37, Matthew J Neville4, Alexandra C Nica5, Ken K Ong1,2, Stephen O'Rahilly2,24, Katharine R Owen4, Colin N A Palmer38, Konstantinos Papadakis26, Simon Potter5, Anneli Pouta31,39, Lu Qi40, Nurses' Health Study71, Joshua C Randall3,4, Nigel W Rayner3,4, Susan M Ring35, Manjinder S Sandhu1,32, André Scherag41, Matthew A Sims1,2, Kijoung Song42, Nicole Soranzo5, Elizabeth K Speliotes43,44, Diabetes Genetics Initiative71, Holly E Syddall18, Sarah A Teichmann20, Nicholas J Timpson3,19, Jonathan H Tobias45, Manuela Uda46, The SardiNIA Study71, Carla I Ganz Vogel28, Chris Wallace36, Dawn M Waterworth42, Michael N Weedon6,7, The Wellcome Trust Case Control Consortium72, Cristen J Willer47, FUSION71, Vicki L Wraight2,24, Xin Yuan42, Eleftheria Zeggini3, Joel N Hirschhorn44,48,49,50,51, David P Strachan26, Willem H Ouwehand8, Mark J Caulfield36, Nilesh J Samani33, Timothy M Frayling6,7, Peter Vollenweider52, Gerard Waeber52, Vincent Mooser42, Panos Deloukas5, Mark I McCarthy3,4,73, Nicholas J Wareham1,2,73 & Inês Barroso5,73

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To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 × 10−6) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 × 10−15) and 5,988 children aged 7–11 (0.13 Z-score units; P = 1.5 × 10−8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 10−11). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 × 10−4). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

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  1. MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  2. Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
  4. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
  5. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  6. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU, UK.
  7. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK.
  8. Department of Haematology, University of Cambridge, and NHS (National Health Service) Blood and Transplant, Cambridge Centre, Long Road, Cambridge, UK.
  9. Department of Medical Genetics, University of Lausanne, 1011, Switzerland.
  10. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011, Switzerland.
  11. Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland.
  12. Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
  13. MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
  14. University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011 Switzerland.
  15. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
  16. CNRS-8090-Institute of Biology, Pasteur Institute, Lille 5900, France.
  17. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
  18. MRC Epidemiology Resource Centre, University of Southampton, Southampton SO16 6YD, UK.
  19. The MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol BS8 2PR, UK.
  20. MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK.
  21. Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
  22. Department of Epidemiology and Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
  23. Department of Public Health Science and General Practice, Fin-90014, University of Oulu, Finland.
  24. Metabolic Research Laboratories, University of Cambridge, Cambridge CB2 0QQ, UK.
  25. Genomic Medicine, Hammersmith Hospital, Imperial College London, London W12 ONN, UK.
  26. Division of Community Health Sciences, St George's, University of London, London SW17 0RE, UK.
  27. LIGHT Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.
  28. Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, D45147 Essen, Germany.
  29. GSF-Institute of Epidemiology, D-85764 Neuherberg-Munich, Germany.
  30. IBE Chair of Epidemiology, University of Munich, D-81377 Munich, Germany.
  31. Department of Child and Adolescent Health, National Public Health Institute, Oulu 90221, Finland.
  32. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 2SR, UK.
  33. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
  34. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
  35. Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK.
  36. Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine, Charterhouse Square, London EC1M 6BQ, UK.
  37. Department of Oral and Dental Science, Bristol Dental School, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, UK.
  38. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
  39. Department of Obstetrics and Gynaecology, University Hospital of Oulu, P.P. Box 22, Oulu 90221, Finland.
  40. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
  41. Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, 45122 Essen, Germany.
  42. Medical Genetics/Clinical Pharmacology and Discovery Medicine, King of Prussia, Pennsylvania 19406, USA.
  43. Department of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
  44. Broad Institute at MIT and Harvard, Boston, Massachusetts 02115, USA.
  45. Clinical Science at South Bristol, University of Bristol, Bristol BS2 8AE, UK.
  46. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari 09100, Italy.
  47. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  48. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  49. Division of Genetics, Children's Hospital, Boston, Massachusetts 02115, USA.
  50. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  51. Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA.
  52. Department of Medicine and Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011, Switzerland.
  53. Bioinformed Consulting Services, Gaithersburg, Maryland 20877, USA.
  54. Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, DHHS, Bethesda, Maryland 20892, USA.
  55. GSF-Institute of Human Genetics, D-85764 Neuherberg-Munich, Germany.
  56. Institute of Human Genetics, Technical University Munich, Munich D-81671, Germany.
  57. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
  58. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
  59. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  60. Department of Medicine, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114, USA.
  61. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  62. Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital Malmö, Lund University, Malmö S-205 02, Sweden.
  63. Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki 00029, Finland.
  64. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  65. Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21244, USA.
  66. Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, 00300 Helsinki, Finland.
  67. Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.
  68. South Ostrobothnia Central Hospital, 60220 Seinäjoki, Finland.
  69. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
  70. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
  71. A full list of authors is provided at the end of the reference list.
  72. A full list of authors is provided in the Supplementary Note online.
  73. These authors contributed equally to this work.

Correspondence to: Inês Barroso5,73 e-mail: ib1@sanger.ac.uk

Correspondence to: Nicholas J Wareham1,2,73 e-mail: nick.wareham@mrc-epid.cam.ac.uk

Correspondence to: Mark I McCarthy3,4,73 e-mail: mark.mccarthy@drl.ox.ac.uk



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