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

Journal name:
Nature Genetics
Volume:
43,
Pages:
753–760
Year published:
DOI:
doi:10.1038/ng.866
Received
Accepted
Published online

Abstract

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.

At a glance

Figures

  1. Manhattan plot showing the significance of association with body fat percentage for SNPs in the stage 1 meta-analysis of all individuals (n = 36,626).
    Figure 1: Manhattan plot showing the significance of association with body fat percentage for SNPs in the stage 1 meta-analysis of all individuals (n = 36,626).

    SNPs are plotted on the x axis according to their position on each chromosome against association with body fat percentage on the y axis (shown as −log10 P). The loci highlighted in blue are the 11 loci that reached an association P < 10−6 in the stage 1 meta-analysis of all individuals, Europeans, men or women and were taken forward for follow-up analyses but did not achieve genome-wide significance (P < 5 × 10−8) in the meta-analyses combining GWAS and follow-up data. The three loci colored in red are those that reached genome-wide significant association (P < 5 × 10−8) in the meta-analyses combining GWAS and follow-up data.

  2. Regional plot of the loci near IRS1, near SPRY2 and in FTO that reached genome-wide significant evidence for association with body fat percentage.
    Figure 2: Regional plot of the loci near IRS1, near SPRY2 and in FTO that reached genome-wide significant evidence for association with body fat percentage.

    The plotted data for the locus near SPRY2 are from the meta-analysis of individuals of European descent only, and the data for the loci near IRS1 and in FTO are from the meta-analysis of all individuals. The rs2943650 (near IRS1), rs534870 (near SPRY2) and rs8050136 (FTO) SNPs that showed the strongest association with body fat percentage are indicated. For the locus near IRS1, rs2972146, rs2943641 and rs2943634, which have been associated with blood levels of HDL cholesterol and triglycerides9, risk of type 2 diabetes10 and risk of coronary artery disease11, respectively, in GWAS meta-analyses, are also indicated. The plot was generated using LocusZoom44 (see URLs).

  3. Association of the body-fat-percentage-decreasing (T) allele of rs2943650 near IRS1 with blood lipids, insulin sensitivity traits, leptin and adiponectin.
    Figure 3: Association of the body-fat-percentage–decreasing (T) allele of rs2943650 near IRS1 with blood lipids, insulin sensitivity traits, leptin and adiponectin.

    The error bars indicate 95% confidence intervals. All traits were inverse normally transformed to approximate normality (mean = 0, s.d. = 1) in men and women separately. All models were adjusted for age and age squared. The numeric values for the associations are presented in Supplementary Table 6. We found a significant difference between men and women for the levels of HDL cholesterol (P = 0.027), triglycerides (P = 0.025) and adiponectin (P = 0.040). InsAUC/GluAUC, insulin area under the curve (AUC) to glucose AUC ratio.

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Author information

Affiliations

  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
  75. Deceased.

    • Leena Peltonen

Contributions

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

Competing financial 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.

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Supplementary information

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  1. Supplementary Text and Figures (1M)

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

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