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Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile

Nature Genetics volume 43, pages 753760 (2011) | Download Citation


Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10−6) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10−26) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10−11) and one near SPRY2 (P = 3 × 10−8). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat–decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

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A full list of Acknowledgments appears in the Supplementary Note. Funding was provided by Academy of Finland (10404, 124243, 129680, 129494, 141005 and 213506); Agency for Health Care Policy Research (HS06516); Althingi (the Icelandic Parliament); American Heart Association (10SDG269004); AstraZeneca; Baltimore Geriatric Research Education and Clinical Centers; Biocentrum Helsinki Foundation; Biotechnology and Biological Sciences Research Council (G20234); British Heart Foundation (PG/07/133/24260, RG/08/008, SP/04/002, SP/07/007/23671); CamStrad; Cancer Research UK; Cedars-Sinai Board of Governors' Chair in Medical Genetics; Centre for Medical Systems Biology (The Netherlands); Centre Hospitalier Universitaire Vaudois (Lausanne); Croatian Ministry of Science, Education and Sport (196-1962766-2747, 216-1080315-0302 and 309-0061194-2023); Department of Health (UK); Department of Veterans Affairs (USA); Emil and Vera Cornell Foundation; Erasmus Medical Center (Rotterdam); Erasmus University (Rotterdam); European Commission (DG XII, FP7/2007-2013, FP7-KBBE-2010-4-266408, HEALTH-F2-2007-201681, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2003-503041, LSHM-CT-2004-512013, QLG1-CT-2001-01252 and QLG2-CT-2002-01254); Finnish Diabetes Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Heart Foundation; Finnish Medical Society; Folkhälsan Research Foundation; Food Standards Agency (UK); Foundation for Life and Health in Finland; German Bündesministerium für Forschung und Technology (01AK803A-H and 01IG07015G); German Federal Ministry of Education and Research; German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823); Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Göteborg Medical Society; Gyllenberg Foundation; Health and Safety Executive (UK); Health Care Centers in Vasa, Närpes and Korsholm; Hjartavernd (the Icelandic Heart Association); John D. and Catherine T. MacArthur Foundation; Knut and Alice Wallenberg Foundation; Leenaards Foundation; Ludwig-Maximilians Universität München; Lundberg Foundation; Medical Research Council (UK); Men's Associates of Hebrew SeniorLife; Ministerio de Ciencia e Innovación (Spain) (SAF-2009 and SAF-2008-02073); Ministry for Health, Welfare and Sports (The Netherlands); Ministry of Education (Finland); Ministry of Education, Culture and Science (The Netherlands); Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Närpes Health Care Foundation; National Institute for Health Research (UK); US National Institutes of Health (USA) (AG13196, DK063491, K23-DK080145, M01-RR00425, N01-AG12100, N01-AG62101, N01-AG62103, N01-AG62106, N01-HC15103, N01-HC25195, N01-HC35129, N01-HC45133, N01-HC55222, N01-HC75150, N01-HC85079 through N01-HC85086, P30-DK072488, R01-AG031890-01, R01-AG18728, R01-AG032098-01A1, R01-AR/AG41398, R01-AR046838, R01-DK06833603, R01-DK075787, R01-DK07568102, R01-HL036310-20A2, R01-HL087652, R01-HL08770003, R01-HL088119, U01-HL080295, U01-HL72515 and U01-HL84756); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (175.010.2005.011 and 911-03-012); Netherlands Organization for the Health Research and Development; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklén Foundation; Petrus and Augusta Hedlunds Foundation; Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Robert Dawson Evans Endowment; Royal Society (UK); Sahlgrenska Center for Cardiovascular and Metabolic Research (A305:188); Sahlgrenska University Hospital Foundation (ALF/LUA); Science Funding programme (UK); Scottish Executive Health Department; Sigrid Juselius Foundation; State of Bavaria; Stroke Association (UK); Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Research Council (K2010-54X-09894-19-3, K2010-52X-20229-05-3 and 2006-3832); Swedish Strategic Foundation; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 310000-112552 and 33CSCO-122661); TEKES (1510/31/06); Torsten and Ragnar Söderberg's Foundation; United Kingdom NIHR Cambridge Biomedical Research Centre; University of Lausanne; University of Maryland General Clinical Research Center (M01 RR 16500); Uppsala University; Västra Götaland Foundation; and Wellcome Trust (077016/Z/05/Z, 084723/Z/08/Z and 091746/Z/10/Z).

Author information

Author notes

    • Leena Peltonen



  1. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.

    • Tuomas O Kilpeläinen
    • , Francis M Finucane
    • , Claudia Langenberg
    • , Jian'an Luan
    • , Jing-Hua Zhao
    • , Nicholas J Wareham
    •  & Ruth J F Loos
  2. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

    • M Carola Zillikens
    • , Karol Estrada
    • , Leonie C Jacobs
    • , André G Uitterlinden
    •  & Fernando Rivadeneira
  3. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.

    • M Carola Zillikens
    • , Karol Estrada
    • , Albert Hofman
    • , André G Uitterlinden
    • , Cornelia M van Duijn
    •  & Fernando Rivadeneira
  4. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

    • Alena Stančákova
    • , Johanna Kuusisto
    •  & Markku Laakso
  5. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Janina S Ried
    • , Angela Döring
    • , Christian Gieger
    • , Norman Klopp
    • , Brigitte Kühnel
    •  & H-Erich Wichmann
  6. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Weihua Zhang
    •  & John C Chambers
  7. Department of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.

    • Jacques S Beckmann
  8. Centre for Bone and Arthritis Research, Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Liesbeth Vandenput
    • , Mattias Lorentzon
    • , Dan Mellström
    •  & Claes Ohlsson
  9. deCODE Genetics, Reykjavik, Iceland.

    • Unnur Styrkarsdottir
    • , Bjarni V Halldorsson
    • , Gudmar Thorleifsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  10. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Yanhua Zhou
    •  & L Adrienne Cupples
  11. Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Kopavogur, Iceland.

    • Albert Vernon Smith
    • , Gudny Eiriksdottir
    •  & Vilmundur Gudnason
  12. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

    • Najaf Amin
    • , Yurii S Aulchenko
    • , Ben A Oostra
    • , Karol Estrada
    • , Albert Hofman
    • , André G Uitterlinden
    • , Cornelia M van Duijn
    •  & Fernando Rivadeneira
  13. Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Sailaja Vedantam
    • , Candace Guiducci
    • , Joel N Hirschhorn
    •  & Elizabeth K Speliotes
  14. Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston, Massachusetts, USA.

    • Sailaja Vedantam
    •  & Joel N Hirschhorn
  15. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • So-Youn Shin
    • , Leena Peltonen
    • , Inês Barroso
    •  & Nicole Soranzo
  16. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Talin Haritunians
  17. Division of Endocrinology, Diabetes & Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Mao Fu
    • , Braxton D Mitchell
    • , Jeffery R O'Connell
    •  & Alan R Shuldiner
  18. Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Mary F Feitosa
    •  & Ingrid B Borecki
  19. Genetic Epidemiology Group, Department of Epidemiology, University College London, London, UK.

    • Meena Kumari
  20. Reykjavik University, Reykjavik, Iceland.

    • Bjarni V Halldorsson
  21. Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.

    • Emmi Tikkanen
    • , Leena Peltonen
    • , Markus Perola
    •  & Samuli Ripatti
  22. Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland.

    • Emmi Tikkanen
    • , Leena Peltonen
    • , Markus Perola
    •  & Samuli Ripatti
  23. King's College London, London, UK.

    • Massimo Mangino
    •  & Timothy D Spector
  24. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh, UK.

    • Caroline Hayward
    •  & Alan F Wright
  25. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Ci Song
    •  & Erik Ingelsson
  26. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Alice M Arnold
    •  & Barbara McKnight
  27. Centre for Population Health Sciences, The University of Edinburgh Medical School, Edinburgh, UK.

    • Harry Campbell
    • , Sarah H Wild
    • , James F Wilson
    •  & Igor Rudan
  28. Framingham Heart Study, Framingham, Massachusetts, USA.

    • L Adrienne Cupples
  29. Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Kathryn E Davis
    •  & Deborah J Clegg
  30. Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) (CB06/03/0010), Girona, Spain.

    • José Manuel Fernández-Real
    •  & José Maria Moreno
  31. Intramural Research Program, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Melissa Garcia
    • , Lauren J Kim
    •  & Tamara B Harris
  32. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
    • , Barbara McKnight
    •  & Bruce M Psaty
  33. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
  34. Centre for Cardiovascular Genetics, Department of Medicine, University College London, London, UK.

    • Steve E Humphries
    •  & Philippa J Talmud
  35. Folkhälsan Research Centre, Helsinki, Finland.

    • Bo Isomaa
  36. Department of Social Services and Health Care, Jakobstad, Finland.

    • Bo Isomaa
  37. Population Studies Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Antti Jula
  38. Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, Massachusetts, USA.

    • David Karasik
    •  & Douglas P Kiel
  39. Department of Clinical Sciences, Lund University, Malmö, Sweden.

    • Magnus K Karlsson
  40. Department of Orthopaedics, Malmö University Hospital, Malmö, Sweden.

    • Magnus K Karlsson
  41. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
    •  & Robert N Luben
  42. Department of Epidemiology and Public Health, University College London, London, UK.

    • Mika Kivimäki
  43. Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  44. Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

    • Östen Ljunggren
  45. Genetic, Research & Development, GlaxoSmithKline, King of Prussia, Philadelphia, USA.

    • Vincent Mooser
    •  & Kijoung S Song
  46. Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Satu Männistö
    •  & Veikko Salomaa
  47. Institute of Cell & Molecular Biosciences, Newcastle University, Newcastle, UK.

    • Laura Pascoe
    •  & Mark Walker
  48. Instituto de Investigaciones Biomédicas, Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC) & Universidad Autónoma de Madrid, Madrid, Spain.

    • Belén Peral
  49. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  50. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  51. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  52. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

    • Bruce M Psaty
  53. University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • David B Savage
    • , Robert K Semple
    • , Antonio Vidal-Puig
    • , Inês Barroso
    •  & Stephen O'Rahilly
  54. Institute for Anthropological Research, Zagreb, Croatia.

    • Tatjana Skaric-Juric
  55. Department of Endocrinology and Metabolism, University Hospital, Reykjavik, Iceland.

    • Gunnar Sigurdsson
  56. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Gunnar Sigurdsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  57. Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Ann-Christine Syvänen
  58. National Genetics Institute (NGI), Centre for Medical Systems Biology (CMSB), Leiden, The Netherlands.

    • Cornelia M van Duijn
  59. Pacific Biosciences, Menlo Park, California, USA.

    • Eric Schadt
  60. Sage Bionetworks, Seattle, Washington, USA.

    • Eric Schadt
  61. Croatian Centre for Global Health, University of Split Medical School, Split, Croatia.

    • Igor Rudan
  62. Gen Info Ltd, Zagreb, Croatia.

    • Igor Rudan
  63. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Alan R Shuldiner
  64. Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.

    • Erik Ingelsson
  65. Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • John-Olov Jansson
  66. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York, USA.

    • Robert C Kaplan
  67. University of Iceland, Reykjavik, Iceland.

    • Vilmundur Gudnason
  68. Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden.

    • Leif Groop
  69. Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.

    • Peter Vollenweider
    •  & Gérard Waeber
  70. National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

    • Jaspal S Kooner
  71. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
  72. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität and Klinikum Großhadern, Munich, Germany.

    • H-Erich Wichmann
  73. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Elizabeth K Speliotes
  74. National Heart, Lung, and Blood Institute and Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline S Fox


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A full list of author contributions appears in the Supplementary Note.

Competing interests

I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. K.S., G.T., U.T. and U.S. are employed by deCODE Genetics. V.M. is a full-time employee of GlaxoSmithKline. G.W. and P.V. received funding from GlaxoSmithKline to build the CoLaus Study.

Corresponding author

Correspondence to Ruth J F Loos.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1–9, Supplementary Figures 1–7 and Supplementary Note.

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