Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci (original) (raw)

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Acknowledgements

Funding for the research undertaken in this study has been received from the Academy of Finland (including grants 77299, 102318, 10493, 118065, 123885, 124243, 129293, 129680, 136895, 139635, 211119, 213506, 251217 and 263836); Agence National de la Recherche; Association de Langue Française pour l'Etude du Diabète et des Maladies Métaboliques; Association Diabèete Risque Vasculaire; Association Française des Diabétiques; the Association of Danish Pharmacies; the Augustinus Foundation; the Becket Foundation; the British Diabetes Association (BDA) Research; the British Heart Foundation; the Central Norway Health Authority; the Central Finland Hospital District; the Center for Inherited Disease Research (CIDR); the City of Kuopio; the City of Leutkirch; Copenhagen County; the Danish Centre for Evaluation and Health Technology Assessment; the Danish Council for Independent Research; the Danish Heart Foundation; the Danish Research Councils; Deutsche Forschungsgemeinschaft (including project ER 155/6-2); the Diabetes Research Foundation; Diabetes UK; the Doris Duke Charitable Foundation; Erasmus Medical Center; Erasmus University; the Estonian government (SF0180142s08); the European Commission (including ENGAGE HEALTH-F4-2007-201413, FP7-201413, FP7-245536, EXGENESIS LSHM-CT-2004-005272, FP6 LSHM_CT_2006_037197, LSHM-CT-2007-037273, Directorate C-Public Health 2004310, DG XII); the European Regional Development Fund; the Federal Ministry of Education and Research, Germany (including FKZ 01GI1128 and FKZ 01EO1001); the Federal Ministry of Health, Germany; the Finnish Diabetes Association; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Medical Society; the Folkhalsan Research Foundation; the Foundation for Life and Health in Finland; the Foundation for Old Servants; the Fredrick och Ingrid Thuring Foundation; the French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Région); the German Center for Diabetes Research; the German Research Council (including grant GRK1041); the German National Genome Research Network; Groupe d'Etude des Maladies Métaboliques et Systémiques; the Health Care Centers in Vasa, Närpes and Korsholm, Finland; the Health Foundation; the Heinz Nixdorf Foundation; Helmholtz Zentrum München; the Helsinki University Central Hospital Research Foundation; the Hospital District of Southwest Finland; the Ib Henriksens Foundation; IngaBritt and Arne Lundberg's Research Foundation (including grant 359); Karolinska Institutet; the Knut and Alice Wallenberg Foundation (including grant KAW 2009.0243); Kuopio University Hospital; the Lundbeck Foundation; the Magnus Bergvall Foundation; the Medical Faculty of University Duisburg-Essen; the Medical Research Council, UK (including grants G0000649 and G0601261); the Ministry for Health, Welfare and Sports, the Netherlands; the Ministry of Education and Culture, Finland (including grants 722 and 627; 2004-2011); the Ministry of Education, Culture and Science, the Netherlands; the Ministry of Health and Prevention, Denmark; the Ministry of Social Affairs and Health, Finland; the Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany; the Munich Center of Health Sciences; the Municipal Health Care Center and Hospital in Jakobstad, Finland; the municipality of Rotterdam, the Netherlands; the Närpes Health Care Foundation; the National Health Screening Service of Norway; the National Heart, Lung, and Blood Institute, USA (including grant numbers/contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, N01HC25195, N02HL64278, R01HL087641, R01HL59367 and R01HL086694); the National Human Genome Research Institute, USA (including grant numbers/contracts U01HG004402 and N01HG65403); the National Institute for Diabetes and Digestive and Kidney Diseases, USA (including grants R01DK078616, U01DK085526, K24DK080140 and R01DK073490); the National Institute for Health and Welfare, Finland; the National Institutes of Health, USA (including grant numbers/contracts HHSN268200625226C, UL1RR025005, R01DK062370, R01DK072193, 1Z01HG000024, AG028555, AG08724, AG04563, AG10175, AG08861, U01HG004399, DK58845, CA055075, DK085545 and DK098032); the Netherlands Genomics Initiative; the Netherlands Organisation for Health Research and Development; the Netherlands Organisation of Scientific Research NOW Investments (including grants 175.010.2005.011, 911-03-012 and 050-060-810); the Nord-Trondelag County Council; the Nordic Center of Excellence in Disease Genetics; the Norwegian Institute of Public Health; the Norwegian Research Council; the Novo Nordisk Foundation; the Ollquist Foundation; the Oxford National Institute for Health Research (NIHR) Biomedical Research Centre; the Paavo Nurmi Foundation; the Paivikki and Sakari Sohlberg Foundation; the Perklen Foundation; the Pirkanmaa Hospital District, Finland; Programme Hospitalier de Recherche Clinique; Programme National de Recherche sur la Diabète; the Research Institute for Diseases in the Elderly (including grant 014-93-015); the Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center; the Royal Swedish Academy of Sciences; Sarstedt, Germany; the Signe and Ane Gyllenberg Foundation; the Sigrid Juselius Foundation; the Slottery Machine Association, Finland; the Social Insurance Institution of Finland; the South OstroBothnia Hospital District; the state of Baden-Württemberg, Germany; the Stockholm County Council (including grant 560183); the Swedish Cultural Foundation, Finland; the Swedish Diabetes Foundation; the Swedish e-science Research Center; the Swedish Foundation for Strategic Research; the Swedish Heart-Lung Foundation; the Swedish Research Council (including grants SFO EXODIAB 2009-1039, 521-2010-3490, 521-2007-4037, 521-2008-2974, ANDIS 825-2010-5983, LUDC 349-2008-6589 and 8691); the Swedish Society of Medicine; the Tore Nilsson Foundation; the Torsten and Ragnar Soderbergs Stiftelser (including grant MT33/09); University Hospital Essen; University of Tromsø; the University College London NIHR Biomedical Research Centre; the UK NIHR Cambridge Biomedical Research Centre; Uppsala University; Uppsala University Hospital; the Vaasa Hospital District; the Velux Foundation; and the Wellcome Trust (including the Biomedical Collections Grant GR072960 and grants 076113, 083948, 090367, 090532, 083270, 086596, 098017, 095101, 098051 and 098381). We are grateful to R. Scharfmann (INSERM U1016, Cochin Institute Paris) for the gift of EndoC βH1 cells and for providing technical support with their maintenance. We thank P. Johnson and the Oxford NIHR Biomedical Research Centre–funded Islet Isolation facility for providing human islets for this study. Detailed acknowledgments are provided in the Supplementary Note.

Author information

Author notes

1. Wen-Hong L Kao, Leena Peltonen and Steven Wiltshire: Deceased.
2. Kyle J Gaulton, Teresa Ferreira, Yeji Lee, Anne Raimondo, Reedik Mägi and Michael E Reschen: These authors contributed equally to this work.
3. Anna L Gloyn, David Altshuler, Michael Boehnke, Tanya M Teslovich, Mark I McCarthy and Andrew P Morris: These authors jointly supervised this work.

Authors and Affiliations

1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
   Kyle J Gaulton, Teresa Ferreira, Anubha Mahajan, N William Rayner, Neil Robertson, Nicola L Beer, Martijn van de Bunt, Cecilia M Lindgren, Joseph Trakalo, Steven Wiltshire, Erik Ingelsson, Peter J Donnelly, Anna L Gloyn, Mark I McCarthy & Andrew P Morris
2. Department of Genetics, Stanford University, Stanford, California, USA
   Kyle J Gaulton
3. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA
   Yeji Lee, Adam Locke, Laura J Scott, Christian Fuchsberger, Phoenix Kwan, Clement Ma, Hyun Min Kang, Gonçalo R Abecasis, Anne U Jackson, Heather M Stringham, Michael Boehnke & Tanya M Teslovich
4. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
   Anne Raimondo, N William Rayner, Neil Robertson, Soren K Thomsen, Jana K Rundle, Nicola L Beer, Martijn van de Bunt, Christopher J Groves, Katharine R Owen, Anna L Gloyn & Mark I McCarthy
5. Estonian Genome Center, University of Tartu, Tartu, Estonia
   Reedik Mägi, Tonu Esko, Evelin Mihailov, Andres Metspalu & Andrew P Morris
6. Nuffield Department of Medicine, Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK
   Michael E Reschen, Anil Chalisey & Christopher A O'Callaghan
7. Wellcome Trust Sanger Institute, Hinxton, UK
   N William Rayner, Sarah Edkins, Cordelia Langford, Leena Peltonen, Eleftheria Zeggini, Samuli Ripatti, Panagiotis Deloukas & Inês Barroso
8. Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK
   Robert A Scott, Sara M Willems, Nicola D Kerrison, Jian'an Luan, John R B Perry, Ruth J F Loos, Claudia Langenberg & Nicholas J Wareham
9. Genomics of Common Disease, Imperial College London, London, UK
   Inga Prokopenko & Philippe Froguel
10. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
    Todd Green, Noël P Burtt, Jason Carey, Andrew T Crenshaw, Jason Flannick, Pierre Fontanillas, George B Grant, Cecilia M Lindgren, Leena Peltonen, Sekar Kathiresan & David Altshuler
11. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Thomas Sparso, Niels Grarup, Christian T Have, Torben Hansen & Oluf Pedersen
12. Lille Institute of Biology, European Genomics Institute of Diabetes, Lille, France
    Dorothee Thuillier, Loic Yengo, Stephane Cauchi & Philippe Froguel
13. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
    Harald Grallert, Simone Wahl, Christian Gieger, Norman Klopp & Thomas Illig
14. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
    Harald Grallert, Simone Wahl, Christian Gieger, Barbara Thorand & Annette Peters
15. German Center for Diabetes Research, Neuherberg, Germany
    Harald Grallert, Simone Wahl, Barbara Thorand & Annette Peters
16. Department of Medicine Solna, Atherosclerosis Research Unit, Karolinska Institutet, Stockholm, Sweden
    Mattias Frånberg, Rona J Strawbridge, Karl Gertow, Olga McLeod, Bengt Sennblad & Anders Hamsten
17. Science for Life Laboratory, Stockholm, Sweden
    Mattias Frånberg & Bengt Sennblad
18. Department for Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden
    Mattias Frånberg
19. Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany
    Hans Kestler
20. Medical Systems Biology, Ulm University, Ulm, Germany
    Hans Kestler
21. Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finland
    Himanshu Chheda, Leena Peltonen, Emmi Tikkanen, Tiinamaija Tuomi, Samuli Ripatti & Leif C Groop
22. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
    Lewin Eisele, Sonali Pechlivanis & Susanne Moebus
23. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
    Stefan Gustafsson & Erik Ingelsson
24. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
    Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Augustine Kong, Unnur Thorsteinsdottir & Kari Stefansson
25. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
    Lu Qi, David J Hunter, Peter Kraft, Liming Liang & Frank B Hu
26. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
    Lu Qi, Rob M van Dam, Paul W Franks, David J Hunter, Qi Sun & Frank B Hu
27. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Lu Qi, David J Hunter, Qi Sun & Frank B Hu
28. Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA
    Lu Qi
29. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
    Lennart C Karssen, Elisabeth M van Leeuwen, Sara M Willems & Cornelia van Duijn
30. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
    Man Li & Wen-Hong L Kao
31. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
    Han Chen, Ching-Ti Liu & Josée Dupuis
32. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
    Han Chen, Peter Kraft & Liming Liang
33. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
    Michael Linderman
34. Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York,, New York, USA
    Yingchang Lu & Ruth J F Loos
35. Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Benjamin F Voight
36. Department of Clinical Science Malmo, Lund University Diabetes Centre, Scania University Hospital, Lund University, Malmo, Sweden
    Peter Almgren, João Fadista, Paul W Franks, Anna Jonsson, Jasmina Kravic, Eero Lindholm, Valeriya Lyssenko, Nikolay N Oskolkov, Petter Storm, Olle Melander, Peter M Nilsson & Leif C Groop
37. Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
    Damiano Baldassarre & Elena Tremoli
38. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy
    Damiano Baldassarre & Elena Tremoli
39. INSERM Centre de Recherche Epidémiologie et Santé des Populations (CESP) U1018, Villejuif, France
    Beverley Balkau
40. University Paris Sud 11, UMRS 1018, Villejuif, France
    Beverley Balkau
41. Faculty of Medicine, University of Iceland, Reykjavik, Iceland
    Rafn Benediktsson, Unnur Thorsteinsdottir & Kari Stefansson
42. Landspitali University Hospital, Reykjavik, Iceland
    Rafn Benediktsson, Astradur B Hreidarsson & Gunnar Sigurðsson
43. Integrated Treatment and Research (IFB) Center for Adiposity Diseases, University of Leipzig, Leipzig, Germany
    Matthias Blüher, Peter Kovacs, Anke Tonjes & Michael Stumvoll
44. Department of Medicine, University of Leipzig, Leipzig, Germany
    Matthias Blüher, Peter Kovacs, Anke Tonjes & Michael Stumvoll
45. German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany
    Heiner Boeing
46. National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA
    Lori L Bonnycastle, Peter S Chines & Francis S Collins
47. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
    Erwin P Bottinger, Omri Gottesman & Ruth J F Loos
48. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France
    Guillaume Charpentier
49. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
    Marilyn C Cornelis
50. Department of Biostatistics, Collaborative Studies Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    David J Couper
51. Saw Swee Hock School of Public Health, National University of Singapore, Singapore
    Rob M van Dam
52. Diabetes Research Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK
    Alex S F Doney & Collin N A Palmer
53. Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK
    Alex S F Doney & Collin N A Palmer
54. Department of Clinical Science Malmo, Lund University Diabetes Centre, Novo Nordisk Scandinavia, Malmo, Sweden
    Mozhgan Dorkhan
55. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
    Johan G Eriksson, Leena Kinnunen, Satu Männistö, Leena Peltonen, Veikko Salomaa, Heikki Koistinen & Jaakko Tuomilehto
56. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
    Johan G Eriksson
57. Unit of General Practice, Helsinki University General Hospital, Helsinki, Finland
    Johan G Eriksson
58. Folkhalsan Research Center, Helsinki, Finland
    Johan G Eriksson & Tiinamaija Tuomi
59. Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA
    Tonu Esko
60. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
    Tonu Esko & Jose C Florez
61. CNRS UMR 8199, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France
    Elodie Eury, Stéphane Lobbens & Philippe Froguel
62. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA
    Caroline Fox & Josée Dupuis
63. Division of Endocrinology and Metabolism, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Caroline Fox
64. Department of Clinical Sciences, Lund University, Malmo, Sweden
    Paul W Franks
65. Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden
    Paul W Franks
66. Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
    Bruna Gigante, Karin Leander & Ulf de Faire
67. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
    Maija Hassinen, Timo A Lakka & Rainer Rauramaa
68. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany
    Christian Herder & Michael Roden
69. German Center for Diabetes Research, partner site Dusseldorf, Dusseldorf, Germany
    Christian Herder & Michael Roden
70. Department of Public Health and General Practice, Nord-Trøndelag Health Study (HUNT) Research Center, Norwegian University of Science and Technology, Levanger, Norway
    Oddgeir L Holmen, Carl G P Platou & Kristian Hveem
71. Cardiovascular Genetics, British Heart Foundation (BHF) Laboratories, Institute of Cardiovascular Sciences, University College London, London, UK
    Steve E Humphries
72. Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA
    David J Hunter & Peter Kraft
73. Steno Diabetes Center, Gentofte, Denmark
    Marit E Jørgensen & Valeriya Lyssenko
74. Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark
    Torben Jørgensen & Allan Linneberg
75. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Torben Jørgensen
76. Faculty of Medicine, University of Aalborg, Aalborg, Denmark
    Torben Jørgensen
77. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
    Norman Klopp & Thomas Illig
78. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
    Peter Lichtner
79. Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
    Allan Linneberg
80. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Allan Linneberg
81. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
    Julia Meyer, Martina Müller-Nurasyid & Konstantin Strauch
82. Biomedical Research Centre Genomics Core Facility, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, Guy's & St Thomas' Hospital, London, UK
    Ghazala Mirza
83. Institute of Human Genetics, University of Bonn, Bonn, Germany
    Thomas W Mühleisen & Markus M Nöthen
84. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
    Thomas W Mühleisen & Markus M Nöthen
85. Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany
    Thomas W Mühleisen
86. Department of Medicine I, University Hospital Grosshadern, Ludwig Maximilians Universität, Munich, Germany
    Martina Müller-Nurasyid
87. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig Maximilians Universität, Neuherberg, Germany
    Martina Müller-Nurasyid & Konstantin Strauch
88. DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
    Martina Müller-Nurasyid & Annette Peters
89. Department of Epidemiology, Murcia Regional Health Council, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain
    Carmen Navarro
90. Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
    Carmen Navarro
91. Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain
    Carmen Navarro
92. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK
    Katharine R Owen, Anna L Gloyn & Mark I McCarthy
93. Cancer Research and Prevention Institute (ISPO), Florence, Italy
    Domenico Palli
94. Department of Internal Medicine, Levanger Hospital, Nord-Trondelag Health Trust, Levanger, Norway
    Carl G P Platou
95. Department of Endocrinology and Diabetology, University Hospital Dusseldorf, Dusseldorf, Germany
    Michael Roden
96. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA
    Douglas Ruderfer
97. Boston University Data Coordinating Center, Boston, Massachusetts, USA
    Denis Rybin
98. University Medical Center Utrecht, Utrecht, the Netherlands
    Yvonne T van der Schouw
99. Icelandic Heart Association, Kopavogur, Iceland
    Gunnar Sigurðsson
100. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
     Alena Stančáková, Johanna Kuusisto & Markku Laakso
101. Department of Clinical Chemistry and Central Laboratory, University of Ulm, Ulm, Germany
     Gerald Steinbach
102. Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland
     Emmi Tikkanen & Samuli Ripatti
103. Department of Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
     Tiinamaija Tuomi
104. Research Program for Diabetes and Obesity, University of Helsinki, Helsinki, Finland
     Tiinamaija Tuomi
105. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
     Roman Wennauer & Eric Sijbrands
106. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK
     Andrew R Wood & Timothy M Frayling
107. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
     Ian Dunham & Ewan Birney
108. Division of Endocrinology, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain
     Lorenzo Pasquali
109. Josep Carreras Leukaemia Research Institute, Badalona, Spain
     Lorenzo Pasquali
110. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
     Lorenzo Pasquali
111. Department of Medicine, Imperial College London, London, UK
     Jorge Ferrer
112. Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centre Esther Koplowitz, Barcelona, Spain
     Jorge Ferrer
113. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
     Ruth J F Loos
114. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
     Jose C Florez, James B Meigs & David Altshuler
115. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA
     Jose C Florez, Sekar Kathiresan & David Altshuler
116. Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
     Jose C Florez & David Altshuler
117. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA
     Eric Boerwinkle
118. Human Genome Sequencing Center at Baylor College of Medicine, Houston, Texas, USA
     Eric Boerwinkle
119. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA
     James S Pankow
120. Netherlands Genomics Initiative, Netherlands Consortium for Healthy Ageing and Center for Medical Systems Biology, Rotterdam, the Netherlands
     Cornelia van Duijn
121. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA
     James B Meigs
122. Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio, Finland
     Timo A Lakka & Karl-Heinz Jöcke
123. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
     Timo A Lakka & Rainer Rauramaa
124. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
     Nancy L Pedersen
125. Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden
     Lars Lind
126. Faculty of Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland
     Sirkka M Keinanen-Kiukaanniemi
127. Unit of General Practice, Oulu University Hospital, Oulu, Finland
     Sirkka M Keinanen-Kiukaanniemi
128. South Ostrobothnia Central Hospital, Seinajoki, Finland
     Eeva Korpi-Hyövälti
129. Finnish Diabetes Association, Tampere, Finland
     Timo E Saaristo
130. Pirkanmaa District Hospital, Tampere, Finland
     Timo E Saaristo
131. Department of Medicine, Central Finland Central Hospital, Jyvasklya, Finland
     Juha Saltevo
132. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
     Andres Metspalu
133. Clinic of Cardiology, West German Heart Centre, University Hospital of Essen, University Duisdurg-Essen, Essen, Germany
     Raimund Erbel
134. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland
     Samuli Ripatti
135. Division of Endocrinology and Diabetes, Department of Internal Medicine, University Medical Centre Ulm, Ulm, Germany
     Bernhard O Boehm
136. Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore
     Bernhard O Boehm
137. Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
     Richard N Bergman
138. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
     Karen L Mohlke
139. Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
     Heikki Koistinen
140. Minerva Foundation Institute for Medical Research, Helsinki, Finland
     Heikki Koistinen
141. Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain
     Jaakko Tuomilehto
142. Centre for Vascular Prevention, Danube University Krems, Krems, Austria
     Jaakko Tuomilehto
143. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
     Jaakko Tuomilehto
144. Department of Community Medicine, Faculty of Health Sciences, University of Tromso, Tromso, Norway
     Inger Njølstad
145. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
     Panagiotis Deloukas
146. Department of Statistics, University of Oxford, Oxford, UK
     Peter J Donnelly
147. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
     Andrew T Hattersley
148. Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
     Rob Sladek
149. McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada
     Rob Sladek
150. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
     Torben Hansen
151. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
     Andrew D Morris
152. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
     Sekar Kathiresan
153. University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, UK
     Inês Barroso
154. National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
     Inês Barroso
155. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
     David Altshuler
156. Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts, USA
     David Altshuler
157. Department of Biostatistics, University of Liverpool, Liverpool, UK
     Andrew P Morris
158. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
     Andrew P Morris

Authors

1. Kyle J Gaulton
2. Teresa Ferreira
3. Yeji Lee
4. Anne Raimondo
5. Reedik Mägi
6. Michael E Reschen
7. Anubha Mahajan
8. Adam Locke
9. N William Rayner
10. Neil Robertson
11. Robert A Scott
12. Inga Prokopenko
13. Laura J Scott
14. Todd Green
15. Thomas Sparso
16. Dorothee Thuillier
17. Loic Yengo
18. Harald Grallert
19. Simone Wahl
20. Mattias Frånberg
21. Rona J Strawbridge
22. Hans Kestler
23. Himanshu Chheda
24. Lewin Eisele
25. Stefan Gustafsson
26. Valgerdur Steinthorsdottir
27. Gudmar Thorleifsson
28. Lu Qi
29. Elisabeth M van Leeuwen
30. Sara M Willems
31. Man Li
32. Han Chen
33. Christian Fuchsberger
34. Phoenix Kwan
35. Clement Ma
36. Michael Linderman
37. Yingchang Lu
38. Soren K Thomsen
39. Jana K Rundle
40. Nicola L Beer
41. Martijn van de Bunt
42. Anil Chalisey
43. Hyun Min Kang
44. Benjamin F Voight
45. Gonçalo R Abecasis
46. Peter Almgren
47. Damiano Baldassarre
48. Beverley Balkau
49. Rafn Benediktsson
50. Matthias Blüher
51. Heiner Boeing
52. Lori L Bonnycastle
53. Erwin P Bottinger
54. Noël P Burtt
55. Jason Carey
56. Guillaume Charpentier
57. Peter S Chines
58. Marilyn C Cornelis
59. David J Couper
60. Andrew T Crenshaw
61. Rob M van Dam
62. Alex S F Doney
63. Mozhgan Dorkhan
64. Sarah Edkins
65. Johan G Eriksson
66. Tonu Esko
67. Elodie Eury
68. João Fadista
69. Jason Flannick
70. Pierre Fontanillas
71. Caroline Fox
72. Paul W Franks
73. Karl Gertow
74. Christian Gieger
75. Bruna Gigante
76. Omri Gottesman
77. George B Grant
78. Niels Grarup
79. Christopher J Groves
80. Maija Hassinen
81. Christian T Have
82. Christian Herder
83. Oddgeir L Holmen
84. Steve E Humphries
85. David J Hunter
86. Anne U Jackson
87. Anna Jonsson
88. Marit E Jørgensen
89. Torben Jørgensen
90. Wen-Hong L Kao
91. Nicola D Kerrison
92. Leena Kinnunen
93. Norman Klopp
94. Augustine Kong
95. Peter Kovacs
96. Peter Kraft
97. Jasmina Kravic
98. Cordelia Langford
99. Karin Leander
100. Liming Liang
101. Peter Lichtner
102. Cecilia M Lindgren
103. Eero Lindholm
104. Allan Linneberg
105. Ching-Ti Liu
106. Stéphane Lobbens
107. Jian'an Luan
108. Valeriya Lyssenko
109. Satu Männistö
110. Olga McLeod
111. Julia Meyer
112. Evelin Mihailov
113. Ghazala Mirza
114. Thomas W Mühleisen
115. Martina Müller-Nurasyid
116. Carmen Navarro
117. Markus M Nöthen
118. Nikolay N Oskolkov
119. Katharine R Owen
120. Domenico Palli
121. Sonali Pechlivanis
122. Leena Peltonen
123. John R B Perry
124. Carl G P Platou
125. Michael Roden
126. Douglas Ruderfer
127. Denis Rybin
128. Yvonne T van der Schouw
129. Bengt Sennblad
130. Gunnar Sigurðsson
131. Alena Stančáková
132. Gerald Steinbach
133. Petter Storm
134. Konstantin Strauch
135. Heather M Stringham
136. Qi Sun
137. Barbara Thorand
138. Emmi Tikkanen
139. Anke Tonjes
140. Joseph Trakalo
141. Elena Tremoli
142. Tiinamaija Tuomi
143. Roman Wennauer
144. Steven Wiltshire
145. Andrew R Wood
146. Eleftheria Zeggini
147. Ian Dunham
148. Ewan Birney
149. Lorenzo Pasquali
150. Jorge Ferrer
151. Ruth J F Loos
152. Josée Dupuis
153. Jose C Florez
154. Eric Boerwinkle
155. James S Pankow
156. Cornelia van Duijn
157. Eric Sijbrands
158. James B Meigs
159. Frank B Hu
160. Unnur Thorsteinsdottir
161. Kari Stefansson
162. Timo A Lakka
163. Rainer Rauramaa
164. Michael Stumvoll
165. Nancy L Pedersen
166. Lars Lind
167. Sirkka M Keinanen-Kiukaanniemi
168. Eeva Korpi-Hyövälti
169. Timo E Saaristo
170. Juha Saltevo
171. Johanna Kuusisto
172. Markku Laakso
173. Andres Metspalu
174. Raimund Erbel
175. Karl-Heinz Jöcke
176. Susanne Moebus
177. Samuli Ripatti
178. Veikko Salomaa
179. Erik Ingelsson
180. Bernhard O Boehm
181. Richard N Bergman
182. Francis S Collins
183. Karen L Mohlke
184. Heikki Koistinen
185. Jaakko Tuomilehto
186. Kristian Hveem
187. Inger Njølstad
188. Panagiotis Deloukas
189. Peter J Donnelly
190. Timothy M Frayling
191. Andrew T Hattersley
192. Ulf de Faire
193. Anders Hamsten
194. Thomas Illig
195. Annette Peters
196. Stephane Cauchi
197. Rob Sladek
198. Philippe Froguel
199. Torben Hansen
200. Oluf Pedersen
201. Andrew D Morris
202. Collin N A Palmer
203. Sekar Kathiresan
204. Olle Melander
205. Peter M Nilsson
206. Leif C Groop
207. Inês Barroso
208. Claudia Langenberg
209. Nicholas J Wareham
210. Christopher A O'Callaghan
211. Anna L Gloyn
212. David Altshuler
213. Michael Boehnke
214. Tanya M Teslovich
215. Mark I McCarthy
216. Andrew P Morris

Consortia

the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

Contributions

Writing group. K.J.G., T.F., Y. Lee, A.R., R.M., M.E.R., A.L.G., D.A., M. Boehnke, T.M.T., M.I.M., A.P.M. Central meta-analysis group. K.J.G., T.F., Y. Lee, R.M., A. Mahajan, A. Locke, N.W.R., N.R., T.M.T., M.I.M., A.P.M. Annotation and functional analysis group. K.J.G., A.R., M.E.R., S.K.T., J.K.R., N.L.B., M.v.d.B., A.C., I.D., E. Birney, L. Pasquali, J. Ferrer, C.A.O'C., A.L.G., M.I.M. Validation meta-analysis group. R.M., R.A.S., I.P., L.J.S., A.P.M. Metabochip cohort-level primary analysis. Y. Lee, T.G., T.S., D.T., L.Y., H.G., S. Wahl, M.F., R.J.S., H. Kestler, H. Chheda, L.E., S.G., T.M.T., A.P.M. Validation cohort-level primary analysis. V. Steinthorsdottir, G.T., L.Q., L.C.K., E.M.v.L., S.M.W., M. Li, H. Chen, C. Fuchsberger, P. Kwan, C.M., M. Linderman, Y. Lu. Metabochip design. H.M.K., B.F.V. Cohort sample collection, genotyping, phenotyping or additional analysis. B.F.V., G.R.A., P.A., D.B., B.B., R.B., M. Blüher, H.B., L.L.B., E.P.B., N.P.B., J.C., G.C., P.S.C., M.C.C., D.J.C., A.T.C., R.M.v.D., A.S.F.D., M.D., S.E., J.G.E., T.E., E.E., J. Fadista, J. Flannick, P. Fontanillas, C. Fox, P.W.F., K.G., C.G., B.G., O.G., G.B.G., N.G., C.J.G., M.H., C.T.H., C.H., O.L.H., A.B.H., S.E.H., D.J.H., A.U.J., A.J., M.E.J., T.J., W.-H.L.K., N.D.K., L.K., N.K., A.K., P. Kovacs, P. Kraft, J. Kravic, C. Langford, K.L., L. Liang, P.L., C.M.L., E.L., A. Linneberg, C.-T.L., S.L., J.L., V.L., S. Männistö, O. McLeod, J.M., E.M., G.M., T.W.M., M.M.-N., C.N., M.M.N., N.N.O., K.R.O., D.P., S.P., L. Peltonen, J.R.B.P., C.G.P.P., M.R., D. Ruderfer, D. Rybin, Y.T.v.d.S., B.S., G. Sigur∂sson, A.S., G. Steinbach, P.S., K. Strauch, H.M.S., Q.S., B.T., E. Tikkanen, A.T., J. Trakalo, E. Tremoli, T.T., R.W., S. Wiltshire, A.R.W., E.Z. Validation cohort principal investigators. R.J.F.L., J.D., J.C.F., E. Boerwinkle, J.S.P., C.v.D., E.S., J.B.M., F.B.H., U.T., K. Stefansson, P.D., P.J.D., T.M.F., A.T.H., I.B., C. Langenberg, N.J.W., M. Boehnke, M.I.M. Metabochip cohort principal investigators. T.A.L., R.R., M.S., N.L.P., L. Lind, S.M.K.-K., E.K.-H., T.E.S., J.S., J. Kuusisto, M. Laakso, A. Metspalu, R.E., K.-H.J., S. Moebus, S.R., V. Salomaa, E.I., B.O.B., R.N.B., F.S.C., K.L.M., H. Koistinen, J. Tuomilehto, K.H., I.N., P.D., P.J.D., T.M.F., A.T.H., U.d.F., A.H., T.I., A.P., S.C., R.S., P. Froguel, O.P., T.H., A.D.M., C.N.A.P., S.K., O. Melander, P.M.N., L.C.G., I.B., C. Langenberg, N.J.W., D.A., M. Boehnke, M.I.M. Project management. K.J.G., A.L.G., D.A., M. Boehnke, T.M.T., M.I.M., A.P.M. DIAGRAM Consortium management. D.A., M. Boehnke, M.I.M.

Corresponding authors

Correspondence toKyle J Gaulton, Mark I McCarthy or Andrew P Morris.

Ethics declarations

Competing interests

V. Steinthorsdottir, G.T., A.K., U.T. and K. Stefansson are employed by deCODE Genetics/Amgen, Inc. I.B. and spouse own stock in GlaxoSmithKline and Incyte.

Additional information

A list of members and affiliations appears in the Supplementary Note.

Integrated supplementary information

Supplementary Figure 1 Signal plots for association signals achieving locus-wide significance at the KCNQ1 locus.

Association summary statistics are based on the meta-analysis of Metabochip studies in 27,206 cases and 57,574 controls of European ancestry. Results are presented from exact conditioning after adjusting for all other index variants at the locus. Each point represents a SNP passing quality control in the meta-analysis, plotted with its conditional P value (on a –log10 scale) as a function of genomic position (NCBI Build 37). In each plot, the index variant is represented by the purple symbol. The color coding of all other SNPs indicates LD with the index variant in European-ancestry haplotypes from the 1000 Genomes Project reference panel: red, _r_2 ≥ 0.8; gold, 0.6 ≤ _r_2 < 0.8; green, 0.4 ≤ _r_2 < 0.6; cyan, 0.2 ≤ _r_2 < 0.4; blue, _r_2 < 0.2; gray, _r_2 unknown. The shape of the symbol corresponds to the annotation of the variant: upward triangle, framestop or splice; downward triangle, nonsynonymous; square, synonymous or UTR; and circle, intronic or noncoding. Recombination rates are estimated from HapMap Phase 2, and gene annotations are taken from the UCSC Genome Browser.

Supplementary Figure 2 Signal plots for association signals achieving locus-wide significance at the HNF1A locus.

Association summary statistics are based on the meta-analysis of Metabochip studies in 27,206 cases and 57,574 controls of European ancestry. Results are presented from exact conditioning after adjusting for all other index variants at the locus. Each point represents a SNP passing quality control in the meta-analysis, plotted with its conditional P value (on a –log10 scale) as a function of genomic position (NCBI Build 37). In each plot, the index variant is represented by the purple symbol. The color coding of all other SNPs indicates LD with the index variant in European-ancestry haplotypes from the 1000 Genomes Project reference panel: red, _r_2 ≥ 0.8; gold, 0.6 ≤ _r_2 < 0.8; green, 0.4 ≤ _r_2 < 0.6; cyan, 0.2 ≤ _r_2 < 0.4; blue, _r_2 < 0.2; gray, _r_2 unknown. The shape of the symbol corresponds to the annotation of the variant: upward triangle, framestop or splice; downward triangle, nonsynonymous; square, synonymous or UTR; and circle, intronic or noncoding. Recombination rates are estimated from HapMap Phase 2, and gene annotations are taken from the UCSC Genome Browser.

Supplementary Figure 3 Signal plots for association signals achieving locus-wide significance at the DGKB, _CDKN2A_-CDKN2B, MC4R and GIPR loci.

Association summary statistics are based on the meta-analysis of Metabochip studies in 27,206 cases and 57,574 controls of European ancestry. Results are presented from exact conditioning after adjusting for all other index variants at the locus. Each point represents a SNP passing quality control in the meta-analysis, plotted with its conditional P value (on a –log10 scale) as a function of genomic position (NCBI Build 37). In each plot, the index variant is represented by the purple symbol. The color coding of all other SNPs indicates LD with the index variant in European-ancestry haplotypes from the 1000 Genomes Project reference panel: red, _r_2 ≥ 0.8; gold, 0.6 ≤ _r_2 < 0.8; green, 0.4 ≤ _r_2 < 0.6; cyan, 0.2 ≤ _r_2 < 0.4; blue, _r_2 < 0.2; gray, _r_2 unknown. The shape of the symbol corresponds to the annotation of the variant: upward triangle, framestop or splice; downward triangle, nonsynonymous; square, synonymous or UTR; and circle, intronic or noncoding. Recombination rates are estimated from HapMap Phase 2, and gene annotations are taken from the UCSC Genome Browser.

Supplementary Figure 4 Signal plots for association signals at the _CDKN2A_-CDKN2B locus.

Association summary statistics are based on the meta-analysis of Metabochip studies in 27,206 cases and 57,574 controls of European ancestry. (a) Unconditional. (b) After approximate conditioning on the two index SNPs, rs10811660 and rs10757283. Each point represents a SNP passing quality control in the meta-analysis, plotted with its conditional P value (on a –log10 scale) as a function of genomic position (NCBI Build 37). In each plot, the index variant is represented by the purple symbol. The color coding of all other SNPs indicates LD with the index variant in European-ancestry haplotypes from the 1000 Genomes Project reference panel: red, _r_2 ≥ 0.8; gold, 0.6 ≤ _r_2 < 0.8; green, 0.4 ≤ _r_2 < 0.6; cyan, 0.2 ≤ _r_2 < 0.4; blue, _r_2 < 0.2; gray, _r_2 unknown. Recombination rates are estimated from HapMap Phase 2, and gene annotations are taken from the UCSC Genome Browser.

Supplementary Figure 5 Characteristics of index variants for association signals achieving locus-wide significance for T2D susceptibility across fine-mapping regions.

Each association signal was represented by an index variant in the GCTA-COJO joint regression model on the basis of (i) summary statistics from the meta-analysis of Metabochip studies in 27,206 cases and 57,574 controls of European ancestry and (ii) reference genotype data from GoDARTS (3,298 cases and 3,708 controls of European ancestry from the UK) to approximate LD across fine-mapping regions. Each variant is plotted according to risk allele frequency on the x axis and allelic log(OR) on the y axis (with error bars representing the corresponding standard error).

Supplementary Figure 6 Characteristics of the 99% credible sets of variants for each association signal achieving locus-wide significance for T2D susceptibility across fine-mapping regions.

Each point corresponds to an association signal, plotted according to the highest posterior probability of causality of any variant in the credible set on the x axis and the total number of variants in the credible set on the y axis. Distinct association signals at loci are referenced according to their index variant.

Supplementary Figure 7 Enrichment in chromatin state and noncoding RNA elements.

Variants in regulatory enhancer, promoter and insulator elements from 12 cell types and noncoding RNA elements from 25 cell types were tested for enrichment of average posterior causal probability compared to variants in shifted elements. Variants in islet enhancer elements demonstrated significant enrichment (fold = 1.97; P = 0.00022), and variants in islet and HepG2 promoter elements demonstrated nominally significant enrichment (P < 0.01).

Supplementary Figure 8 Null distribution of enriched transcription factors.

Null distribution of mean posterior probabilities of driving association signals for variants in shifted annotations (blue bars) compared to observed mean probability (dashed line) for the most significantly enriched transcription factors.

Supplementary Figure 9 FOXA2 ChIP-seq sites overlap, genome wide, across cell types.

The number of FOXA2 sites identified in ChIP-seq assays from primary pancreatic islets, HepG2 cells and primary liver was obtained, and sites from each cell type were intersected.

Supplementary Figure 10 Electrophoretic mobility shift assay of rs10830963 in HepG2 cellular extracts.

Nuclear extract (NE) from HepG2 cells was treated with labeled probes of 25 bp of sequence containing each allele of rs10830963. We observed protein bands bound to both sequences (black) as well as bands unique to the non-risk (red) and risk (blue) sequences. We then introduced antibodies against HNF3B (FOXA2 alias) and four factors (YY1, TAL1, NEURDO1 and PTF1A) whose known binding motifs match the de novo motif at rs10830963. We observed no shifting of the allele-specific bands with any antibody. Several bands shared by both alleles were removed in the presence of antibody to YY1.

Supplementary Figure 11 Genes at FOXA2-enriched signals are downregulated in Foxa1/Foxa2 null mice.

Pancreatic islet gene expression data were obtained from wild-type and Foxa1/Foxa2 knockout mice (Gao et al.47). Genes within 500 kb of each FOXA2-enriched T2D signal and closest to each FOXA2-enriched signal (orange) were significantly downregulated in the Foxa1/Foxa2 knockout compared to all genes (gray).

Supplementary Figure 12 Comparison of summary statistics for association signals achieving locus-wide significance from the GCTA-COJO joint regression model using genotype data from two reference studies to approximate LD between variants across each fine-mapping region.

Association summary statistics are based on the meta-analysis of Metabochip studies in 27,206 cases and 57,574 controls of European ancestry. Association summary statistics were obtained using (i) 3,298 T2D cases and 3,708 controls of UK ancestry from GoDARTS (represented on the x axis) and (ii) 4,435 T2D cases and 5,757 controls of Scandinavian ancestry from FUSION (represented on the y axis). Left, comparison of P values (_P_J) from the GCTA-COJO joint regression model. Right, comparison of allelic log(OR) (blue diamond) and standard error (gray error bars) from the GCTA-COJO joint regression model.

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Gaulton, K., Ferreira, T., Lee, Y. et al. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.Nat Genet 47, 1415–1425 (2015). https://doi.org/10.1038/ng.3437

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• Received: 01 December 2014
• Accepted: 07 October 2015
• Published: 09 November 2015
• Issue date: December 2015
• DOI: https://doi.org/10.1038/ng.3437