• A Corrigendum to this article was published on 31 January 2017

This article has been updated

Abstract

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

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Change history

  • 05 December 2016

    In the version of this article initially published online, the middle initial of collaborator Maarten R. Soeters was inadvertently omitted. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We are grateful for the OP9-K cells kindly shared by the laboratory of A. Kopin (Tufts Medical Center). The authors gratefully acknowledge the help of the MRC Epidemiology Unit Support Teams, including the Field Teams, the Laboratory Team and the Data Management Team, and of the staff of the Wellcome Trust Clinical Research Facility.

This study was funded by the UK Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC_UU_12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372). Funding for the InterAct project was provided by the EU FP6 program (grant LSHM_CT_2006_037197). This work was funded, in part, through an EFSD Rising Star award to R.A.S. supported by Novo Nordisk. D.B.S. is supported by Wellcome Trust grant 107064. M.I.M. is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. M.v.d.B. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. I.B. is supported by Wellcome Trust grant WT098051. S.O'R. acknowledges funding from the Wellcome Trust (Wellcome Trust Senior Investigator Award 095515/Z/11/Z and Wellcome Trust Strategic Award 100574/Z/12/Z).

AUTHOR CONTRUBUTIONS

Concept and design: L.A.L., I.B., N.J.W., D.B.S., C.L., S.O'R. and R.A.S. Generation, acquisition, analysis and/or interpretation of data: all authors. Drafting of the manuscript: L.A.L., I.B., N.J.W., D.B.S., C.L., S.O'R. and R.A.S. Critical review of the manuscript for important intellectual content and approval of the final version of the manuscript: all authors.

Author information

Author notes

    • Nicholas J Wareham
    • , Stephen O'Rahilly
    • , David B Savage
    • , Inês Barroso
    • , Nicholas J Wareham
    • , David B Savage
    • , Claudia Langenberg
    • , Stephen O'Rahilly
    •  & Robert A Scott

    These authors contributed equally to this work

Affiliations

  1. MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

    • Luca A Lotta
    • , Felix R Day
    • , Stephen J Sharp
    • , Jian'an Luan
    • , Emanuella De Lucia Rolfe
    • , Isobel D Stewart
    • , Sara M Willems
    • , Claudia Langenberg
    • , Robert A Scott
    • , Nita G Forouhi
    • , Nicola D Kerrison
    • , Matt Sims
    • , Debora M E Lucarelli
    • , Nicholas J Wareham
    •  & John R B Perry
  2. Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

    • Pawan Gulati
    • , Claire Adams
    • , Inês Barroso
    • , Panos Deloukas
    • , Robert K Semple
    • , Stephen O'Rahilly
    •  & David B Savage
  3. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Felicity Payne
    • , Eleanor Wheeler
    •  & Inês Barroso
  4. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

    • Halit Ongen
    •  & Emmanouil Dermitzakis
  5. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Martijn van de Bunt
    •  & Mark I McCarthy
  6. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Martijn van de Bunt
    •  & Mark I McCarthy
  7. Department of Pediatrics, University of California at San Diego, La Jolla, California, USA.

    • Kyle J Gaulton
  8. Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

    • John D Eicher
    •  & Andrew D Johnson
  9. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK.

    • Hanieh Yaghootkar
    •  & Timothy Frayling
  10. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
  11. Public Health Division of Gipuzkoa, San Sebastian, Spain.

    • Larraitz Arriola
  12. Instituto BIO-Donostia, Basque Government, San Sebastian, Spain.

    • Larraitz Arriola
  13. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

    • Larraitz Arriola
    • , Aurelio Barricarte
    • , Carmen Navarro
    •  & Elena Salamanca-Fernández
  14. INSERM, CESP, U1018, Villejuif, France.

    • Beverley Balkau
  15. Université Paris–Sud, UMRS 1018, Villejuif, France.

    • Beverley Balkau
  16. Navarre Public Health Institute (ISPN), Pamplona, Spain.

    • Aurelio Barricarte
  17. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.

    • Aurelio Barricarte
  18. German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.

    • Heiner Boeing
  19. Lund University, Malmö, Sweden.

    • Paul W Franks
  20. Umeå University, Umeå, Sweden.

    • Paul W Franks
    •  & Olov Rolandsson
  21. Catalan Institute of Oncology (ICO), Barcelona, Spain.

    • Carlos Gonzalez
  22. Epidemiology and Prevention Unit, Milan, Italy.

    • Sara Grioni
  23. German Cancer Research Centre (DKFZ), Heidelberg, Germany.

    • Rudolf Kaaks
  24. Nuffield Department of Population Health, University of Oxford, Oxford, UK.

    • Timothy J Key
  25. Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.

    • Carmen Navarro
  26. Unit of Preventive Medicine and Public Health, School of Medicine, University of Murcia, Murcia, Spain.

    • Carmen Navarro
  27. Department of Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden.

    • Peter M Nilsson
  28. Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.

    • Kim Overvad
  29. Aalborg University Hospital, Aalborg, Denmark.

    • Kim Overvad
  30. Cancer Research and Prevention Institute (ISPO), Florence, Italy.

    • Domenico Palli
  31. Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.

    • Salvatore Panico
  32. Public Health Directorate, Oviedo, Spain.

    • J Ramón Quirós
  33. Unit of Cancer Epidemiology, Città della Salute e della Scienza Hospital, University of Turin, and Center for Cancer Prevention (CPO), Turin, Italy.

    • Carlotta Sacerdote
  34. Human Genetics Foundation (HuGeF), Turin, Italy.

    • Carlotta Sacerdote
  35. Andalusian School of Public Health, Granada, Spain.

    • Elena Salamanca-Fernández
  36. Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Granada, Spain.

    • Elena Salamanca-Fernández
  37. International Agency for Research on Cancer, Lyon, France.

    • Nadia Slimani
  38. Danish Cancer Society Research Center, Copenhagen, Denmark.

    • Anne Tjonneland
  39. ASP Ragusa, Ragusa, Italy.

    • Rosario Tumino
  40. National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

    • Annemieke M W Spijkerman
    •  & Daphne L van der A
  41. University Medical Center Utrecht, Utrecht, the Netherlands.

    • Yvonne T van der Schouw
  42. School of Public Health, Imperial College London, London, UK.

    • Elio Riboli
  43. Wolfson Diabetes and Endocrine Clinic, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

    • Anna Stears
    • , Ellie Gurnell
    •  & Amanda Adler
  44. East and North Herts NHS Trust, Lister Hospital, Herts, UK.

    • Stella George
  45. Institute of Cellular Medicine (Diabetes), Newcastle University Medical School, Newcastle-upon-Tyne, UK.

    • Mark Walker
  46. Harrogate and District Hospital, Harrogate, UK.

    • Deirdre Maguire
  47. James Cook University Hospital, Middlesborough, UK.

    • Rasha Mukhtar
    •  & Sath Nag
  48. Department of Endocrinology and Metabolism, Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.

    • Maarten R Soeters
  49. St Richard's Hopsital, Chichester, UK.

    • Ken Laji
  50. North Devon District Hospital, Raleigh Park, Barnstaple, UK.

    • Alistair Watt
  51. King's College Hospital, London, UK.

    • Simon Aylwin
  52. Department of Diabetes and Endocrinology, Southmead Hospital, Bristol, UK.

    • Andrew Johnson
  53. Ipswich Hospital, Ipswich, UK.

    • Gerry Rayman
  54. University Hospital of North Midlands NHS Trust, Royal Stoke University Hospital, Stoke-on-Trent, UK.

    • Fahmy Hanna
  55. Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

    • Sian Ellard
  56. Medical School, University of Sheffield, Sheffield, UK.

    • Richard Ross
  57. Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Zagreb, Croatia.

    • Kristina Blaslov
    •  & Lea Smirčić Duvnjak

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  1. EPIC-InterAct Consortium

  2. Cambridge FPLD1 Consortium

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The authors declare no competing financial interests.

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Correspondence to Inês Barroso or Nicholas J Wareham or David B Savage or Claudia Langenberg or Stephen O'Rahilly or Robert A Scott.

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Published

DOI

https://doi.org/10.1038/ng.3714

Further reading