Article | Published:

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Nature Genetics volume 44, pages 659669 (2012) | Download Citation

Abstract

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

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Acknowledgements

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

Author information

Author notes

    • Leena Peltonen

    Deceased.

    • Alisa K Manning
    • , Marie-France Hivert
    •  & Robert A Scott

    These authors contributed equally to this work.

    • James B Meigs
    •  & Claudia Langenberg

    These authors jointly directed this work.

Affiliations

  1. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Alisa K Manning
    • , Han Chen
    • , Ching-Ti Liu
    •  & Josée Dupuis
  2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Alisa K Manning
    • , Aarno Palotie
    • , Richa Saxena
    • , Benjamin F Voight
    •  & Jose C Florez
  3. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Alisa K Manning
  4. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Alisa K Manning
  5. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Marie-France Hivert
    • , Jonna L Grimsby
    •  & James B Meigs
  6. Department of Medicine, Universite de Sherbrooke, Sherbrooke, Québec, Canada.

    • Marie-France Hivert
  7. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Robert A Scott
    • , Daniel Barnes
    • , Nita G Forouhi
    • , Ruth J F Loos
    • , Jian'an Luan
    • , Ken K Ong
    • , Nicholas J Wareham
    •  & Claudia Langenberg
  8. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Jonna L Grimsby
    • , Jose C Florez
    •  & James B Meigs
  9. Institut Pasteur de Lille, Lille, France.

    • Nabila Bouatia-Naji
    • , Cecile Lecoeur
    • , Elodie Eury
    • , Philippe Froguel
    •  & Stéphane Lobbens
  10. Université Lille Nord de France, Lille, France.

    • Nabila Bouatia-Naji
    • , Cecile Lecoeur
    • , Elodie Eury
    • , Philippe Froguel
    •  & Stéphane Lobbens
  11. Boston University Data Coordinating Center, Boston, Massachusetts, USA.

    • Denis Rybin
  12. Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.

    • Lawrence F Bielak
    • , Min A Jhun
    • , Sharon L R Kardia
    •  & Patricia A Peyser
  13. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Inga Prokopenko
    • , Vasiliki Lagou
    • , Reedik Mägi
    •  & Mark I McCarthy
  14. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Inga Prokopenko
    • , Vasiliki Lagou
    • , John R B Perry
    • , Anuj Goel
    • , Reedik Mägi
    • , John F Peden
    • , Hugh Watkins
    •  & Mark I McCarthy
  15. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Najaf Amin
    • , Cornelia M van Duijn
    • , Yurii Aulchenko
    • , Albert Hofman
    • , Andre G Uitterlinden
    • , Sara M Willems
    •  & Jacqueline C M Witteman
  16. Genetic Epidemiology and Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Gemma Cadby
    •  & Lyle J Palmer
  17. Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.

    • Gemma Cadby
    •  & Lyle J Palmer
  18. Netherlands Twin Register, VU University, Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga
    • , Dorret I Boomsma
    • , Eco de Geus
    •  & Gonneke Willemsen
  19. Department of Biological Psychology, VU University, Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga
    • , Dorret I Boomsma
    • , Eco de Geus
    •  & Gonneke Willemsen
  20. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Erik Ingelsson
    • , Patrik K E Magnusson
    • , Nancy L Pedersen
    •  & Emil Rehnberg
  21. Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Anne U Jackson
    •  & Michael Boehnke
  22. Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Toby Johnson
  23. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Stavroula Kanoni
    • , Panos Deloukas
    • , Aarno Palotie
    • , Leena Peltonen
    •  & Kathleen Stirrups
  24. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Malmö, Sweden.

    • Claes Ladenvall
    • , Dmitry Shungin
    • , Paul W Franks
    • , Leif Groop
    • , Ola Hansson
    •  & Valeriya Lyssenko
  25. Lund University Diabetes Centre, Malmö, Sweden.

    • Claes Ladenvall
    • , Dmitry Shungin
    • , Paul W Franks
    • , Leif Groop
    • , Ola Hansson
    •  & Valeriya Lyssenko
  26. Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.

    • Jari Lahti
    •  & Katri Räikkönen
  27. Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  28. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.

    • Maria Teresa Martinez-Larrad
    • , Arturo Corbatón-Anchuelo
    •  & Manuel Serrano-Rios
  29. Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • May E Montasser
    • , Jeff O'Connell
    •  & Alan R Shuldiner
  30. MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.

    • Pau Navarro
    • , Caroline Hayward
    • , Veronique Vitart
    •  & Alan F Wright
  31. Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

    • John R B Perry
    • , Timothy M Frayling
    •  & Hanieh Yaghootkar
  32. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • John R B Perry
    •  & Kerrin S Small
  33. Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

    • Laura J Rasmussen-Torvik
  34. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Perttu Salo
    • , Antti Jula
    • , Markus Perola
    •  & Veikko Salomaa
  35. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

    • Naveed Sattar
  36. Department of Public Health & Clinical Medicine, Genetic Epidemiology & Clinical Research Group, Umeå University Hospital, Umeå, Sweden.

    • Dmitry Shungin
    •  & Paul W Franks
  37. Department of Odontology, Umeå University, Umeå, Sweden.

    • Dmitry Shungin
  38. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

    • Rona J Strawbridge
    • , Anders Hamsten
    • , Maria Sabater-Lleal
    •  & Bengt Sennblad
  39. Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Toshiko Tanaka
  40. Centre for Medical Systems Biology, Netherlands Genomics Initiative, The Hague, The Netherlands.

    • Cornelia M van Duijn
  41. Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, Rotterdam, The Netherlands.

    • Cornelia M van Duijn
    • , Albert Hofman
    • , Andre G Uitterlinden
    •  & Jacqueline C M Witteman
  42. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri, USA.

    • Ping An
    • , Ingrid B Borecki
    •  & Michael A Province
  43. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Mariza de Andrade
  44. Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Jeanette S Andrews
  45. Icelandic Heart Association, Kopavogur, Iceland.

    • Thor Aspelund
    • , Gudny Eiriksdottir
    • , Vilmundur Gudnason
    •  & Albert Vernon Smith
  46. University of Iceland, Reykjavik, Iceland.

    • Thor Aspelund
    • , Vilmundur Gudnason
    •  & Albert Vernon Smith
  47. Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.

    • Mustafa Atalay
    •  & Timo Lakka
  48. Institut de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Épidémiologie et Santé des Populations (CESP) Centre for Research in Epidemiology and Population Health, Villejuif, France.

    • Beverley Balkau
  49. University Paris–Sud 11, Unité Mixte de Recherche en Santé (UMRS) 1018, Villejuif, France.

    • Beverley Balkau
  50. Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.

    • Stefania Bandinelli
  51. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Jacques S Beckmann
  52. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

    • Jacques S Beckmann
  53. PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, Queen Elizabeth II (QEII) Medical Centre, Nedlands, Western Australia, Australia.

    • John P Beilby
    •  & Jennie Hui
  54. School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, Western Australia, Australia.

    • John P Beilby
  55. Busselton Population Medical Research Foundation, B Block, QEII Medical Centre, Nedlands, Western Australia, Australia.

    • John P Beilby
    •  & Joseph Hung
  56. Texas Biomedical Research Institute, San Antonio, Texas, USA.

    • Claire Bellis
    •  & John Blangero
  57. Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

    • Richard N Bergman
    •  & Richard M Watanabe
  58. Department of Pharmacology, Faculty of Medicine, University of Split, Split, Croatia.

    • Mladen Boban
    •  & Danijela Budimir
  59. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
  60. Genome Technology Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Lori L Bonnycastle
    • , Peter S Chines
    • , Francis S Collins
    • , Michael R Erdos
    • , Mario A Morken
    • , Narisu Narisu
    •  & Amy J Swift
  61. Integriertes Forschungs- und Behandlungszentrum (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.

    • Yvonne Böttcher
    • , Michael Stumvoll
    •  & Anke Tönjes
  62. Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.

    • Claude Bouchard
  63. Department of Epidemiology & Public Health, University College London, London, UK.

    • Eric Brunner
    • , Mika Kivimaki
    •  & Michael Marmot
  64. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

    • Harry Campbell
    • , Igor Rudan
    • , Sarah H Wild
    • , James F Wilson
    •  & Lina Zgaga
  65. Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland, USA.

    • Olga Carlson
    •  & Josephine M Egan
  66. Clinical Trial Service Unit, University of Oxford, Oxford, UK.

    • Robert Clarke
  67. Department of Biostatistics, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, USA.

    • David Couper
  68. Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Ulf de Faire
    • , Bruna Gigante
    • , Karin Leander
    •  & Max Vikström
  69. Department of Nutrition–Dietetics, Harokopio University, Athens, Greece.

    • George V Dedoussis
    •  & Maria Dimitriou
  70. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan G Eriksson
  71. Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.

    • Johan G Eriksson
  72. Folkhalsan Research Centre, Helsinki, Finland.

    • Johan G Eriksson
  73. Vaasa Central Hospital, Vaasa, Finland.

    • Johan G Eriksson
  74. National Institute for Health and Welfare, Helsinki, Finland.

    • Johan G Eriksson
    •  & Jaakko Kaprio
  75. Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Luigi Ferrucci
  76. Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.

    • Ian Ford
    •  & Paul C D Johnson
  77. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Caroline S Fox
    •  & Josée Dupuis
  78. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline S Fox
  79. Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy.

    • Maria Grazia Franzosi
  80. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Paul W Franks
  81. Institut National de la Recherche Agronomique, Université Paris, Bobigny Cedex, France.

    • Paul W Franks
  82. Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK.

    • Philippe Froguel
  83. INSERM, Université Paris, Bobigny Cedex, France.

    • Pilar Galan
    •  & Serge Hercberg
  84. Department of Medicine, Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Nicole L Glazer
  85. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Nicole L Glazer
  86. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.

    • Anuj Goel
    •  & John F Peden
  87. Department of Public Health & Clinical Medicine, Nutrition Research, Umeå University, Umeå, Sweden.

    • Göran Hallmans
    •  & Hugh Watkins
  88. Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA.

    • Tamara B Harris
    •  & Lenore J Launer
  89. Centre National de Génotypage, Commissariat à l'Energie Atomique, Institut de Génomique, Evry, France.

    • Simon Heath
    • , G Mark Lathrop
    •  & Diana Zelenika
  90. Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. (Affiliated Institute of the University Lübeck).

    • Andrew A Hicks
    •  & Peter P Pramstaller
  91. Genetic Epidemiology Group, Department of Epidemiology & Public Health, University College London, London, UK.

    • Aroon Hingorani
    •  & Meena Kumari
  92. School of Population Health, The University of Western Australia, Nedlands, Western Australia, Australia.

    • Jennie Hui
  93. Sir Charles Gairdner Hospital Unit, School of Medicine & Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia.

    • Joseph Hung
  94. Department of Epidemiology and Biostatistics, School of Public Health, MRC–Health Protection Agency (HPA) Centre for Environment and Health, Faculty of Medicine, Imperial College London, London, UK.

    • Marjo-Riitta Jarvelin
  95. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  96. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  97. National Institute of Health and Welfare, Oulu, Finland.

    • Marjo-Riitta Jarvelin
  98. Department of Cardiology C5-P, Leiden University Medical Center, Leiden, The Netherlands.

    • J Wouter Jukema
    •  & Stella Trompet
  99. Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.

    • J Wouter Jukema
  100. Division of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA.

    • W H Kao
  101. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
    • , Aarno Palotie
    • , Leena Peltonen
    •  & Elisabeth Widen
  102. Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.

    • Jaakko Kaprio
  103. Faculty of Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Sirkka Keinanen-Kiukaanniemi
  104. Unit of General Practice, Oulu University Hospital, Oulu, Finland.

    • Sirkka Keinanen-Kiukaanniemi
  105. Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.

    • Ivana Kolcic
    •  & Ozren Polasek
  106. Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany.

    • Peter Kovacs
  107. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

    • Johanna Kuusisto
    • , Markku Laakso
    •  & Alena Stančáková
  108. Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.

    • Kirsten Ohm Kyvik
  109. Odense Patient data Explorative Network (OPEN), University of Southern Denmark, Odense, Denmark.

    • Kirsten Ohm Kyvik
  110. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.

    • Timo Lakka
    •  & Rainer Rauramaa
  111. Department of Public Health and Caring Sciences, Uppsala University, Rudbecklaboratoriet, Uppsala, Sweden.

    • Lars Lannfelt
  112. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Guo Li
    •  & David S Siscovick
  113. Department of Medical Sciences, University Hospital, Uppsala University, Uppsala, Sweden.

    • Lars Lind
  114. Diabetes Prevention Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaana Lindstrom
    •  & Jaakko Tuomilehto
  115. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Reedik Mägi
  116. INSERM, Centre de Recherche des Cordeliers, Paris, France.

    • Pierre Meneton
  117. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Karen L Mohlke
  118. Division of Genetics, GlaxoSmithKline, Philadelphia, Pennsylvania, USA.

    • Vincent Mooser
    •  & Dawn M Waterworth
  119. Department of Epidemiology, Center for Aging and Population Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Iva Miljkovic
  120. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Ben A Oostra
  121. Department of Medical Genetics, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

    • Aarno Palotie
  122. Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota, USA.

    • James S Pankow
  123. Department of Biology, Faculty of Medicine, University of Split, Split, Croatia.

    • Marina Pehlic
    •  & Tatijana Zemunik
  124. Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.

    • Brenda Penninx
  125. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Brenda Penninx
  126. Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.

    • Brenda Penninx
    •  & Johannes H Smit
  127. Institute for Research in Extramural Medicine (EMGO Institute) for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.

    • Brenda Penninx
  128. Institute for Anthropological Research, Zagreb, Croatia.

    • Marijana Pericic
  129. Department of Preventive Medicine, Laval University, Quebec City, Quebec, Canada.

    • Louis Perusse
  130. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.

    • Rainer Rauramaa
  131. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Ken Rice
  132. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, Calfornia, USA.

    • Jerome I Rotter
  133. Centre for Global Health, University of Split, Split, Croatia.

    • Igor Rudan
  134. Institute of Clinical Medicine, University of Oulu, Oulu, Finland.

    • Aimo Ruokonen
  135. Finnish Diabetes Association, Tampere, Finland.

    • Timo Saaristo
  136. Pirkanmaa Hospital District and Diabetes Center, Tampere, Finland.

    • Timo Saaristo
  137. Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • David B Savage
    •  & Ines Barroso
  138. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Richa Saxena
    •  & Jose C Florez
  139. Department of Medicine, Division Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.

    • Peter Schwarz
  140. Leibniz Institute for Arteriosclerosis Research, University of Munster, Munster, Germany.

    • Udo Seedorf
  141. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Alan R Shuldiner
  142. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Eric J G Sijbrands
    •  & Andre G Uitterlinden
  143. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • David S Siscovick
    •  & Nicholas L Smith
  144. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • David S Siscovick
    •  & Nicholas L Smith
  145. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

    • Nicholas L Smith
  146. Seattle Epidemiologic Research and Information Center, Veterans Affairs Office of Research and Development, Seattle, Washington, USA.

    • Nicholas L Smith
  147. Division of Endocrinology and Diabetes, Department of Medicine, University of Leipzig, Leipzig, Germany.

    • Michael Stumvoll
    •  & Anke Tönjes
  148. Department of Epidemiology, Emory University, Atlanta, Georgia, USA.

    • Yan V Sun
  149. South Ostrobothnia Central Hospital, Seinäjoki, Finland.

    • Jaakko Tuomilehto
  150. Hospital Universitario La Paz, Madrid, Spain.

    • Jaakko Tuomilehto
  151. Centre for Vascular Prevention, Danube–University Krems, Krems, Austria.

    • Jaakko Tuomilehto
  152. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

    • Matti Uusitupa
  153. Research Unit, Kuopio University Hospital, Kuopio, Finland.

    • Matti Uusitupa
  154. Department of Food Science and Nutrition, Laval University, Quebec City, Quebec, Canada.

    • Marie-Claude Vohl
  155. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

    • Peter Vollenweider
    •  & Gerard Waeber
  156. Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Eleanor Wheeler
    •  & Ines Barroso
  157. Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Zagreb, Croatia.

    • Lina Zgaga
  158. Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  159. Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

    • Richard M Watanabe
  160. Diabetes Unit, Diabetes Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jose C Florez

Consortia

  1. DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

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

  2. The Multiple Tissue Human Expression Resource (MUTHER) Consortium

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

Authors

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Contributions

A.K.M., J.D. and J.B.M. conceived of the study, A.K.M. and R.A.S. performed the analysis, A.K.M., M.F.H. and R.A.S. wrote the manuscript, J.B.M. and C. Langenberg directed the work, and J.L.G., N.B.-N., H.C., D.R., C.-T.L., L.F.B., I.P., R.M.W., J.C.F., J.D., J.B.M. and C. Langenberg provided analytical advice and revised the manuscript.

Competing interests

J.C.F. has received consulting fees from Novartis, Eli Lilly and Pfizer. I.B. and spouse own stock in GlaxoSmithKline and Incyte Ltd. A.R.S. is a consultant for Merck.

Corresponding authors

Correspondence to James B Meigs or Claudia Langenberg.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note and Supplementary Figures 1–3

Excel files

  1. 1.

    Supplementary Table 1

    Study descriptives of samples included in meta-analysis

  2. 2.

    Supplementary Table 2

    Meta-analysis results of loci with known associations with glycemic traits

  3. 3.

    Supplementary Table 3

    Meta-analysis results of fasting insulin and fasting glucose loci taken to the follow-up stage of analysis

  4. 4.

    Supplementary Table 4

    Association results of index SNPs with other traits (HOMA-IR, HOMA-B, 2hr glucose, and HbA1c) in MAGIC

  5. 5.

    Supplementary Table 5

    eQTL SNPs in linkage disequilibrium with fasting insulin index SNPs in gene expression database from liver tissue

  6. 6.

    Supplementary Table 6

    Fasting insulin index SNPs in gene expression eQTL database from subcutaneous adipose tissue (MuTHER).

  7. 7.

    Supplementary Table 7

    Details of coding SNPs (cSNPs) near index SNPs.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.2274

Further reading