Letter | Published:

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

Nature Genetics volume 40, pages 768775 (2008) | Download Citation

Abstract

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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Acknowledgements

We acknowledge support of the UK Medical Research Council, the Wellcome Trust, Diabetes UK, Cancer Research United Kingdom, BDA Research, UK National Health Service Research and Development, the European Commission, the Academy of Finland, the British Heart Foundation, the National Institutes of Health, the Novartis Institutes for BioMedical Research, GlaxoSmithKline and the German National Genome Research Net. Personal support was provided by NIDDK (E.K.S., H.N.L., J.N.H., F.S.C.), the Wellcome Trust (A.T.H., E.Z.), Diabetes UK (R.M.F.), the Throne-Holst Foundation (C.M.L.), the Vandervell Foundation (M.N.W.), American Diabetes Association (C.J.W.), Unilever Corporate Research (S.L.) and the British Heart foundation (N.J.S).

Author information

Author notes

    • Ruth J F Loos
    • , Cecilia M Lindgren
    • , Shengxu Li
    • , Mark I McCarthy
    • , Nicholas J Wareham
    •  & Inês Barroso

    These authors contributed equally to this work.

Affiliations

  1. MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

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

    • Ruth J F Loos
    • , Shengxu Li
    • , Jing Hua Zhao
    • , I Sadaf Farooqi
    • , Ken K Ong
    • , Stephen O'Rahilly
    • , Matthew A Sims
    • , Vicki L Wraight
    •  & Nicholas J Wareham
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

    • Cecilia M Lindgren
    • , Inga Prokopenko
    • , Amanda J Bennett
    • , Katherine S Elliott
    • , David M Evans
    • , Christopher J Groves
    • , Blanca Herrera
    • , Joshua C Randall
    • , Nigel W Rayner
    • , Nicholas J Timpson
    • , Eleftheria Zeggini
    •  & Mark I McCarthy
  4. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Cecilia M Lindgren
    • , Inga Prokopenko
    • , Amanda J Bennett
    • , Christopher J Groves
    • , Blanca Herrera
    • , Fredrik Karpe
    • , Matthew J Neville
    • , Katharine R Owen
    • , Joshua C Randall
    • , Nigel W Rayner
    •  & Mark I McCarthy
  5. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

    • Eleanor Wheeler
    • , Michael Inouye
    • , Antony P Attwood
    • , Emmanouil T Dermitzakis
    • , Jilur Ghori
    • , Rhian Gwilliam
    • , Sarah E Hunt
    • , Andrew Keniry
    • , Ralph McGinnis
    • , Alexandra C Nica
    • , Simon Potter
    • , Nicole Soranzo
    • , Panos Deloukas
    •  & Inês Barroso
  6. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU, UK.

    • Rachel M Freathy
    • , Andrew T Hattersley
    • , Michael N Weedon
    •  & Timothy M Frayling
  7. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK.

    • Rachel M Freathy
    • , Andrew T Hattersley
    • , Michael N Weedon
    •  & Timothy M Frayling
  8. Department of Haematology, University of Cambridge, and NHS (National Health Service) Blood and Transplant, Cambridge Centre, Long Road, Cambridge, UK.

    • Antony P Attwood
    • , Jennifer D M Jolley
    •  & Willem H Ouwehand
  9. Department of Medical Genetics, University of Lausanne, 1011, Switzerland.

    • Jacques S Beckmann
    • , Sven Bergmann
    •  & Toby Johnson
  10. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011, Switzerland.

    • Jacques S Beckmann
  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.

    • Sonja I Berndt
    • , Stephen J Chanock
    •  & Richard B Hayes
  12. Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.

    • Sven Bergmann
    •  & Toby Johnson
  13. MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.

    • Sheila A Bingham
  14. University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011 Switzerland.

    • Murielle Bochud
    •  & Toby Johnson
  15. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • Morris Brown
  16. CNRS-8090-Institute of Biology, Pasteur Institute, Lille 5900, France.

    • Stéphane Cauchi
    • , Christian Dina
    • , Philippe Froguel
    •  & David Meyre
  17. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK.

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

    • Cyrus Cooper
    • , Ian Day
    •  & Holly E Syddall
  19. The MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol BS8 2PR, UK.

    • George Davey Smith
    • , David M Evans
    •  & Nicholas J Timpson
  20. MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK.

    • Subhajyoti De
    •  & Sarah A Teichmann
  21. Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.

    • Alex S F Doney
    •  & Andrew D Morris
  22. Department of Epidemiology and Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.

    • Paul Elliott
    •  & Marjo-Riitta Jarvelin
  23. Department of Public Health Science and General Practice, Fin-90014, University of Oulu, Finland.

    • Paul Elliott
    •  & Marjo-Riitta Jarvelin
  24. Metabolic Research Laboratories, University of Cambridge, Cambridge CB2 0QQ, UK.

    • I Sadaf Farooqi
    • , Stephen O'Rahilly
    •  & Vicki L Wraight
  25. Genomic Medicine, Hammersmith Hospital, Imperial College London, London W12 ONN, UK.

    • Philippe Froguel
  26. Division of Community Health Sciences, St George's, University of London, London SW17 0RE, UK.

    • David Hadley
    • , Konstantinos Papadakis
    •  & David P Strachan
  27. LIGHT Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.

    • Alistair S Hall
  28. Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, D45147 Essen, Germany.

    • Johannes Hebebrand
    • , Anke Hinney
    •  & Carla I Ganz Vogel
  29. GSF-Institute of Epidemiology, D-85764 Neuherberg-Munich, Germany.

    • Iris M Heid
    • , Claudia Lamina
    • , Christian Gieger
    • , Thomas Illig
    •  & H-Erich Wichmann
  30. IBE Chair of Epidemiology, University of Munich, D-81377 Munich, Germany.

    • Iris M Heid
    • , Christian Gieger
    •  & H-Erich Wichmann
  31. Department of Child and Adolescent Health, National Public Health Institute, Oulu 90221, Finland.

    • Marjo-Riitta Jarvelin
    •  & Anneli Pouta
  32. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 2SR, UK.

    • Kay-Tee Khaw
    • , Robert N Luben
    •  & Manjinder S Sandhu
  33. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.

    • Massimo Mangino
    •  & Nilesh J Samani
  34. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.

    • Jonathan Marchini
  35. Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK.

    • Wendy L McArdle
    •  & Susan M Ring
  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.

    • Patricia B Munroe
    • , Chris Wallace
    •  & Mark J Caulfield
  37. Department of Oral and Dental Science, Bristol Dental School, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, UK.

    • Andrew R Ness
  38. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.

    • Colin N A Palmer
  39. Department of Obstetrics and Gynaecology, University Hospital of Oulu, P.P. Box 22, Oulu 90221, Finland.

    • Anneli Pouta
  40. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Lu Qi
    • , David J Hunter
    •  & Frank B Hu
  41. Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, 45122 Essen, Germany.

    • André Scherag
  42. Medical Genetics/Clinical Pharmacology and Discovery Medicine, King of Prussia, Pennsylvania 19406, USA.

    • Kijoung Song
    • , Dawn M Waterworth
    • , Xin Yuan
    •  & Vincent Mooser
  43. Department of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Elizabeth K Speliotes
  44. Broad Institute at MIT and Harvard, Boston, Massachusetts 02115, USA.

    • David J Hunter
    • , Elizabeth K Speliotes
    • , Helen N Lyon
    • , Benjamin F Voight
    •  & Joel N Hirschhorn
  45. Clinical Science at South Bristol, University of Bristol, Bristol BS2 8AE, UK.

    • Jonathan H Tobias
  46. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari 09100, Italy.

    • Manuela Uda
    • , Serena Sanna
    •  & Giuseppe Albai
  47. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Cristen J Willer
    • , Anne U Jackson
    •  & Michael Boehnke
  48. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Helen N Lyon
    •  & Joel N Hirschhorn
  49. Division of Genetics, Children's Hospital, Boston, Massachusetts 02115, USA.

    • Joel N Hirschhorn
  50. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Helen N Lyon
    •  & Joel N Hirschhorn
  51. Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA.

    • Joel N Hirschhorn
  52. Department of Medicine and Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011, Switzerland.

    • Peter Vollenweider
    •  & Gerard Waeber
  53. Bioinformed Consulting Services, Gaithersburg, Maryland 20877, USA.

    • Kevin B Jacobs
  54. Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, DHHS, Bethesda, Maryland 20892, USA.

    • Stephen J Chanock
  55. GSF-Institute of Human Genetics, D-85764 Neuherberg-Munich, Germany.

    • Thomas Meitinger
  56. Institute of Human Genetics, Technical University Munich, Munich D-81671, Germany.

    • Thomas Meitinger
  57. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Peter Kraft
    •  & David J Hunter
  58. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

    • Susan E Hankinson
    • , David J Hunter
    •  & Frank B Hu
  59. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Benjamin F Voight
  60. Department of Medicine, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114, USA.

    • Benjamin F Voight
  61. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Benjamin F Voight
  62. Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital Malmö, Lund University, Malmö S-205 02, Sweden.

    • Martin Ridderstrale
    •  & Leif Groop
  63. Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki 00029, Finland.

    • Leif Groop
  64. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Paul Scheet
    •  & Goncalo R Abecasis
  65. Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21244, USA.

    • Ramaiah Nagaraja
    •  & David Schlessinger
  66. Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, 00300 Helsinki, Finland.

    • Jaakko Tuomilehto
  67. Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.

  68. South Ostrobothnia Central Hospital, 60220 Seinäjoki, Finland.

    • Jaakko Tuomilehto
  69. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.

    • Francis S Collins
  70. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Karen L Mohlke

Consortia

  1. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

  2. KORA

  3. Nurses' Health Study

  4. Diabetes Genetics Initiative

  5. The SardiNIA Study

  6. The Wellcome Trust Case Control Consortium

    A full list of authors is provided in the Supplementary Note.

  7. FUSION

    A full list of authors is provided at the end of the reference list.

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Contributions

Writing team: R.J.F.L., C.M.L., S.L., M.I.M., N.J.W., I.B.

Project management: R.J.F.L., C.M.L., P.D., M.I.M., N.J.W., I.B.

Genome-wide association sampling, genotyping and analysis: R.J.F.L., C.M.L., S.L., E.W., J.H.Z., I.P., M.I., A.P.A., J.S.B., S.B., S.A.B., M. Bochud, M. Brown, J.M.C., D.M.E., J.G., R.G., D.H., A.S.H., A.T.H., S.E.H., T.J., J.D.M.J., A.K., K.-T.K., R.L., M.M., J.M., W.L.M., R.M., P.B.M., A.C.N., K.K.O., K.P., S.P., S.M.R., M.S.S., M.A.S., K.S., N.S., N.J.T., C.W., D.M.W., M.N.W., The Wellcome Trust Case Control Consortium, X.Y., E.Z., D.P.S., W.H.O., M.J.C., N.J.S., T.M.F., P.V., G.W., V.M., P.D., M.I.M., N.J.W., I.B., A.J.B.

Replication samples, genotyping and analysis in adults: R.J.F.L., C.M.L., S.L., R.M.F., A.P.A., A.B., S.C., C.C., G.D.S., I.D., C.D., A.S.F.D., P.E., D.M.E., P.F., C.J.G., A.T.H., M.-R.J., J.D.M.J., F.K., D.M., A.D.M., M.J.N., K.K.O., S.O., K.R.O., C.N.A.P., A.P., A.R.N., S.M.R., M.S.S., M.A.S., H.E.S., N.J.T., M.N.W., V.L.W., E.Z., W.H.O., T.M.F., M.I.M., N.J.W., I.B.

GIANT Consortium samples, genotyping and analysis: S.I.B., K.B.J., S.J.C., R.B.H., I.M.H., C.L., C.G., T.I., T.M., H.-E.W., L.Q., P K., S.E.H., D.J.H., F.B.H, E.K.S., H.N.L., B.F.V., M.R., L.G., J.N.H., M.U., P.S., S.S., G.R.A., G.A., R.N., D.S., C.J.W., A.U. J., J.T., F.S.C., M. Boehnke., K.L.M., FUSION, DGI, PLCO, NHS, SardiNIA.

Replication samples, analysis and genotyping in children: R.M.F., S.C., G.D.S., I.D., C.D., I.S.F., P.F., A.T.H., J.H., A.H., D.M., A.R.N., K.K.O., S.O., S.M.R., A.S., N.J.T., J.H.T., V.L.W., T.M.F., C.I.G.V.

Statistical analysis and informatics: R.J.F.L., C.M.L., S.L., J.H.Z., I.P., R.M.F., S.D., E.T.D., K.S.E., B.H., S.E.H., T.J., J.M., R.M., S.P., J.C.R., N.W.R., A.S., S.A.T., N.J.T., E.Z., M.I.M., N.J.W., I.B.

Competing interests

Vincent Mooser, Dawn Waterworth and Kijoung Song are full-time employees of GlaxoSmithKline.

Peter Vollenweider and Gérard Waeber received financial support from GlaxoSmithKline to build the CoLaus study.

Corresponding authors

Correspondence to Mark I McCarthy or Nicholas J Wareham or Inês Barroso.

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https://doi.org/10.1038/ng.140

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