Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Kyle J. Gaulton, Teresa Ferreira, Yeji Lee, Anne Raimondo, Reedik Mägi, Michael E. Reschen, Anubha Mahajan, Adam Locke, N. William Rayner, Neil Robertson, Robert A. Scott, Inga Prokopenko, Laura J. Scott, Todd Green, Thomas Sparso, Dorothee Thuillier, Loic Yengo, Harald Grallert, Simone Wahl, Mattias FrånbergRona J. Strawbridge, Hans Kestler, Himanshu Chheda, Lewin Eisele, Stefan Gustafsson, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Lu Qi, Lennart C. Karssen, Elisabeth M. Van Leeuwen, Sara M. Willems, Man Li, Han Chen, Christian Fuchsberger, Phoenix Kwan, Clement Ma, Michael Linderman, Yingchang Lu, Soren K. Thomsen, Jana K. Rundle, Nicola L. Beer, Martijn Van De Bunt, Anil Chalisey, Hyun Min Kang, Benjamin F. Voight, Gonçalo R. Abecasis, Peter Almgren, Damiano Baldassarre, Beverley Balkau, Rafn Benediktsson, Matthias Blüher, Heiner Boeing, Lori L. Bonnycastle, Erwin P. Bottinger, Noël P. Burtt, Jason Carey, Guillaume Charpentier, Peter S. Chines, Marilyn C. Cornelis, David J. Couper, Andrew T. Crenshaw, Rob M. Van Dam, Alex S F Doney, Mozhgan Dorkhan, Sarah Edkins, Johan G. Eriksson, Tonu Esko, Elodie Eury, João Fadista, Jason Flannick, Pierre Fontanillas, Caroline Fox, Paul W. Franks, Karl Gertow, Christian Gieger, Bruna Gigante, Omri Gottesman, George B. Grant, Niels Grarup, Christopher J. Groves, Maija Hassinen, Christian T. Have, Christian Herder, Oddgeir L. Holmen, Astradur B. Hreidarsson, Steve E. Humphries, David J. Hunter, Anne U. Jackson, Anna Jonsson, Marit E. Jørgensen, Torben Jørgensen, Wen Hong L Kao, Nicola D. Kerrison, Leena Kinnunen, Norman Klopp, Augustine Kong, Peter Kovacs, Peter Kraft, Jasmina Kravic, Cordelia Langford, Karin Leander, Liming Liang, Peter Lichtner, Cecilia M. Lindgren, Eero Lindholm, Allan Linneberg, Ching Ti Liu, Stéphane Lobbens, Jian'fan Luan, Valeriya Lyssenko, Satu Männistö, Olga McLeod, Julia Meyer, Evelin Mihailov, Ghazala Mirza, Thomas W. Mühleisen, Martina Müller-Nurasyid, Carmen Navarro, Markus M. Nöthen, Nikolay N. Oskolkov, Katharine R. Owen, Domenico Palli, Sonali Pechlivanis, Leena Peltonen, John R B Perry, Carl G P Platou, Michael Roden, Douglas Ruderfer, Denis Rybin, Yvonne T. Van Der Schouw, Bengt Sennblad, Gunnar Sigurosson, Alena Stančáková, Gerald Steinbach, Petter Storm, Konstantin Strauch, Heather M. Stringham, Qi Sun, Barbara Thorand, Emmi Tikkanen, Anke Tonjes, Joseph Trakalo, Elena Tremoli, Tiinamaija Tuomi, Roman Wennauer, Steven Wiltshire, Andrew R. Wood, Eleftheria Zeggini, Ian Dunham, Ewan Birney, Lorenzo Pasquali, Jorge Ferrer, Ruth J F Loos, Josée Dupuis, Jose C. Florez, Eric Boerwinkle, James S. Pankow, Cornelia Van Duijn, Eric Sijbrands, James B. Meigs, Frank B. Hu, Unnur Thorsteinsdottir, Kari Stefansson, Timo A. Lakka, Rainer Rauramaa, Michael Stumvoll, Nancy L. Pedersen, Lars Lind, Sirkka M. Keinanen-Kiukaanniemi, Eeva Korpi-Hyövälti, Timo E. Saaristo, Juha Saltevo, Johanna Kuusisto, Markku Laakso, Andres Metspalu, Raimund Erbel, Karl Heinz Jöckel, Susanne Moebus, Samuli Ripatti, Veikko Salomaa, Erik Ingelsson, Bernhard O. Boehm, Richard N. Bergman, Francis S. Collins, Karen L. Mohlke, Heikki Koistinen, Jaakko Tuomilehto, Kristian Hveem, Inger Njølstad, Panagiotis Deloukas, Peter J. Donnelly, Timothy M. Frayling, Andrew T. Hattersley, Ulf De Faire, Anders Hamsten, Thomas Illig, Annette Peters, Stephane Cauchi, Rob Sladek, Philippe Froguel, Torben Hansen, Oluf Pedersen, Andrew D. Morris, Collin N A Palmer, Sekar Kathiresan, Olle Melander, Peter M. Nilsson, Leif C. Groop, Inês Barroso, Claudia Langenberg, Nicholas J. Wareham, Christopher A. O'Callaghan, Anna L. Gloyn, David Altshuler, Michael Boehnke, Tanya M. Teslovich, Mark I. McCarthy, Andrew P. Morris

Research output: Contribution to journalArticlepeer-review

219 Scopus citations

Abstract

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Original languageEnglish (US)
Pages (from-to)1415-1425
Number of pages11
JournalNature Genetics
Volume47
Issue number12
DOIs
StatePublished - Dec 1 2015

Bibliographical note

Funding Information:
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

Funding Information:
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

Funding Information:
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.

Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

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