Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
2015; Nature Portfolio; Volume: 47; Issue: 12 Linguagem: Inglês
10.1038/ng.3437
ISSN1546-1718
AutoresKyle J. Gaulton, Teresa Ferreira, Yeji Lee, Anne Raimondo, Reedik Mägi, Michael E. Reschen, Anubha Mahajan, Adam E. Locke, Nigel W. Rayner, Neil Robertson, Robert A. Scott, Inga Prokopenko, Laura J. Scott, Todd Green, Thomas Sparsø, Dorothée Thuillier, Loïc Yengo, Harald Grallert, Simone Wahl, Mattias Frånberg, Rona J. Strawbridge, Hans A. Kestler, Himanshu Chheda, Lewin Eisele, Stefan Gustafsson, Valgerður Steinthórsdóttir, Guðmar Þorleifsson, Lu Qi, Lennart C. Karssen, Jin‐Moo Lee, Sara M. Willems, Man Li, Han Chen, Christian Fuchsberger, Phoenix Kwan, Clement Ma, Michael D. 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. Böttinger, Noël P. Burtt, Jason Carey, G. Charpentier, Peter S. Chines, Marilyn C. Cornelis, David Couper, Andrew Crenshaw, Rob M. van Dam, Alex S. F. Doney, Mozhgan Dorkhan, Sarah Edkins, Johan G. Eriksson, Tõnu Esko, Elodie Eury, João Fadista, Jason Flannick, Pierre Fontanillas, Caroline S. Fox, Paul W. Franks, Karl Gertow, Christian Gieger, Bruna Gigante, Omri Gottesman, George Grant, Niels Grarup, Christopher J. Groves, Maija Hassinen, Henri Theil, Christian Herder, Oddgeir L. Holmen, Ástráður B. Hreiðarsson, Steve E. Humphries, Sarah Hunt, Anne Jackson, Anna Jonsson, Marit E. Jørgensen, Torben Jørgensen, Wen‐Hong L. Kao, Nicola D. Kerrison, Leena Kinnunen, Norman Klopp, Augustine Kong, Péter Kovács, Peter Kraft, Jasmina Kravić, Cordelia Langford, Karin Leander, Liming Liang, Peter Lichtner, Cecilia M. Lindgren, Eero Lindholm, Allan Linneberg, Yongmei Liu, Stéphane Lobbens, Jian’an Luan, Valeriya Lyssenko, Satu Männistö, Olga McLeod, Julia Meyer, Evelin Mihailov, Ghazala Mirza, Hae‐Won Uh, Martina Müller‐Nurasyid, Carmen Navarro, Markus M. Nöthen, Nikolay Oskolkov, Katharine R. Owen, Domenico Palli, Sonali Pechlivanis, Leena Peltonen, John R. B. Perry, Carl G. P. Platou, Michael Roden, Douglas M. Ruderfer, Denis Rybin, Yvonne T. van der Schouw, Bengt Sennblad, Gunnar Sigurðsson, Alena Stančáková, Gerald Steinbach, Petter Storm, Konstantin Strauch, Heather M. Stringham, Qi Sun, Barbara Thorand, Emmi Tikkanen, Anke Tönjes, Joseph Trakalo, Elena Tremoli, Jaakko Tuomilehto, Roman Wennauer, Steven Wiltshire, Andrew R. Wood, Eleftheria Zeggini, Ian Dunham, Ewan Birney, Lorenzo Pasquali, Jorge Ferrer, Ruth J. F. Loos, Josée Dupuis, José C. Florez, Eric Boerwinkle, James S. Pankow, Cornelia M. van Duijn, Eric J.G. Sijbrands, James B. Meigs, Frank B. Hu, Unnur Þorsteinsdóttir, Kári Stéfansson, Timo A. Lakka, Rainer Rauramaa, Michael Stümvoll, Nancy L. Pedersen, Lars Lind, Sirkka Keinänen‐Kiukaanniemi, Eeva Korpi-Hyövälti, Timo Saaristo, Juha Saltevo, Johanna Kuusisto, Markku Laakso, Andres Metspalu, Raimund Erbel, Karl-Heinz Jöcke, Susanne Moebus, Samuli Ripatti, Veikko Salomaa, Erik Ingelsson, Bernhard O. Boehm, Richard N. Bergman, Francis S. Collins, Karen L. Mohlke, Heikki A. Koistinen, Jaakko Tuomilehto, Kristian Hveem, Inger Njølstad, Panos Deloukas, Peter Donnelly, Timothy M. Frayling, Andrew T. Hattersley, Ulf dé Fairé, Anders Hamsten, Thomas Illig, Annette Peters, Stéphane Cauchi, Robert Sladek, Philippe Froguel, Torben Hansen, Oluf Pedersen, Andrew D. Morris, Nicholette D. Palmer, Sekar Kathiresan, Olle Melander, Peter M. Nilsson, Leif 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,
Tópico(s)Genetic Mapping and Diversity in Plants and Animals
ResumoKyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk. 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.
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