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

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

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Yvonne van der Schouw
van Leeuwen et al., 2015

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Nature Research, Nature Genetics, 12(47), p. 1415-1425, 2015

DOI: 10.1038/ng.3437

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@article{van Leeuwen2015,
  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.},
  author = {van Leeuwen, Elisabeth M. and van Dam, Rob M. and van de Bunt, Martijn and van der Schouw, Yvonne T. and van Duijn, Cornelia and de Faire, Ulf and William Rayner, N. and Scott, Robert A. and Raimondo, Anne and Scott, Laura J. and Reschen, Michael E. and Rayner, Nw William and Sparso, Thomas and Strawbridge, Rona J. and Thuillier, Dorothee and Yengo, Loic and Willems, Sara M. and Wahl, Simone and Robertson, Neil and Steinthorsdottir, Valgerdur and Prokopenko, Inga and Thorleifsson, Gudmar and Thomsen, Soren K. and Rundle, Jana K. and Qi, Lu and Van Leeuwen, E. M. and Voight, Benjamin F. and Van De Bunt, M. and Van Dam, R. M. and Sigurðsson, Gunnar and Stringham, Heather M. and Roden, Michael and Ruderfer, Douglas and Rybin, Denis and Sennblad, Bengt and Stančáková, Alena and Steinbach, Gerald and Storm, Petter and Wood, Andrew R. and Strauch, Konstantin and Sun, Qi and Thorand, Barbara and Tikkanen, Emmi and Tonjes, Anke and Zeggini, Eleftheria and Trakalo, Joseph and Tremoli, Elena and Tuomi, Tiinamaija and Van Der Schouw, Y. T. and Sigurosson, G. and Wennauer, Roman and Wiltshire, Steven and Saaristo, Timo E. and Sijbrands, Eric and Thorsteinsdottir, Unnur and Stefansson, Kari and Stumvoll, Michael and Ra, Scott and Van Duijn, C. and Saltevo, Juha and Rauramaa, Rainer and Salomaa, Veikko and Tuomilehto, Jaakko and Ripatti, Samuli and Wareham, Nicholas J. and Sladek, Rob and Teslovich, Tanya M. and Gaulton, Kyle J. and Ferreira, Teresa and Lee, Yeji and Maegi, Reedik and Mahajan, Anubha and Locke, Adam and Kestler, Hans and Chheda, Himanshu and Eisele, Lewin and Mägi, Reedik and Gustafsson, Stefan and Grallert, Harald and Karssen, Lennart C. and Green, Todd and Li, Man and Frånberg, Mattias and Chen, Han and Fuchsberger, Christian and Kwan, Phoenix and Ma, Clement and Kj, Gaulton and Linderman, Michael and Lu, Yingchang and Beer, Nicola L. and Blueher, Matthias and Kang, Hyun Min and Chalisey, Anil and Abecasis, Gonçalo R. and Almgren, Peter and Baldassarre, Damiano and Balkau, Beverley and Benediktsson, Rafn and Boeing, Heiner and Bottinger, Erwin P. and Bonnycastle, Lori Ll and Burtt, Noël P. and Carey, Jason and Franberg, Mattias and Charpentier, Guillaume and Chines, Peter S. and Cornelis, Marilyn C. and Couper, David J. and Crenshaw, Andrew T. and Blüher, Matthias and Doney, Alex Sf F. and Dorkhan, Mozhgan and Edkins, Sarah and Eriksson, Johan G. and Esko, Tonu and Eury, Elodie and Fadista, João and Flannick, Jason and Fontanillas, Pierre and Fox, Caroline and Gertow, Karl and Gieger, Christian and Franks, Paul W. and Gigante, Bruna and Clement,  and Gottesman, Omri and Grarup, Niels and Hassinen, Maija and Herder, Christian and Grant, George B. and Me, Reschen and Hreidarsson, Astradur B. and Groves, Christopher J. and Jorgensen, Marit E. and Have, Christian T. and Jorgensen, Torben and Holmen, Oddgeir L. and Jonsson, Anna and Humphries, Steve E. and Kinnunen, Leena and Klopp, Norman and Hunter, David J. and Kong, Augustine and Kovacs, Peter and Jackson, Anne U. and Kraft, Peter and Kravic, Jasmina and Langford, Cordelia and Kao, Wen-Hong L. and Leander, Karin and Jørgensen, Torben and Kerrison, Nicola D. and Liang, Liming and Lichtner, Peter and Lindholm, Eero and Linneberg, Allan and Platou, Carl Gp P. and Peltonen, Leena and Lobbens, Stéphane and Luan, Jian'an and Lyssenko, Valeriya and Perry, John Rb B. and McLeod, Olga and Meyer, Julia and Lindgren, Cecilia M. and Borringer, Erwin P. and Mihailov, Evelin and Mirza, Ghazala and Jørgensen, Marit E. and Liu, Ching-Ti and Männistö, Satu and Navarro, Carmen and Oskolkov, Nikolay Nn and Nw, Rayner and Palli, Domenico and Müller-Nurasyid, Martina and Mannisto, Satu and Pechlivanis, Sonali and Nöthen, Markus Mm and Owen, Katharine R. and Muehleisen, Thomas W. and Mühleisen, Thomas W. and Mueller-Nurasyid, Martina and Noethen, Markus M. and Dunham, Ian and Birney, Ewan and Pasquali, Lorenzo and Ferrer, Jorge and Dupuis, Josée and Loos, Ruth Jf F. and Boerwinkle, Eric and Florez, Jose C. and Pedersen, Nancy L. and Pankow, James S. and Meigs, James B. and Mӓnnistö, Satu and Hu, Frank B. and Lakka, Timo A. and Lj, Scott and Lind, Lars and Korpi-Hyövälti, Eeva and Keinanen Kiukaanniemi, Sirkka M. and Kuusisto, Johanna and Laakso, Markku and Metspalu, Andres and Erbel, Raimund and Moebus, Susanne and Ingelsson, Erik and Jöckel, Karl-Heinz and Joecke, Karl-Heinz and Bergman, Richard N. and Boehm, Bernhard O. and Collins, Francis S. and Koistinen, Heikki and Mohlke, Karen L. and Hveem, Kristian and Njølstad, Inger and Peters, Annette and Deloukas, Panagiotis and Donnelly, Peter J. and De Faire, U. and Jöcke, Karl-Heinz and Frayling, Timothy M. and Hamsten, Anders and Hattersley, Andrew T. and Pedersen, Oluf and Illig, Thomas and Cauchi, Stephane and Froguel, Philippe and Hansen, Torben and Morris, Andrew D. and Palmer, Collin Na A. and Kathiresan, Sekar and Melander, Olle and Nilsson, Peter M. and Groop, Leif C. and Barroso, Inês and Langenberg, Claudia and O'Callaghan, Christopher A. and O’Callaghan, Christopher A. and Gloyn, Anna L. and Altshuler, David and Boehnke, Michael and McCarthy, Mark I. and Consortium, DIAbetes Genetics Replication And Meta-Analysis (Diagram) and Morris, Andrew P. and DIAbet Genetics Replication Meta, A. and Price, Jackie},
  doi = {10.1038/ng.3437},
  journal = {Nature Genetics},
  month = {nov},
  pages = {1415-1425},
  title = {Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci},
  url = {http://www.nature.com/articles/ng.3437.pdf},
  volume = {47},
  year = {2015}
}

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

Journal article published in 2015 by Elisabeth M. van Leeuwen, Rob M. van Dam, Martijn van de Bunt, Yvonne T. van der Schouw

, Cornelia van Duijn, Ulf de Faire, N. William Rayner, Robert A. Scott, Anne Raimondo, Laura J. Scott, Michael E. Reschen, Nw William Rayner, Thomas Sparso, Rona J. Strawbridge, Dorothee Thuillier and other authors. Elisabeth M. van Leeuwen, Rob M. van Dam, Martijn van de Bunt, Yvonne T. van der Schouw

, Cornelia van Duijn, Ulf de Faire, N. William Rayner, Robert A. Scott, Anne Raimondo, Laura J. Scott, Michael E. Reschen, Nw William Rayner, Thomas Sparso, Rona J. Strawbridge, Dorothee Thuillier, Loic Yengo, Sara M. Willems, Simone Wahl, Neil Robertson, Valgerdur Steinthorsdottir, Inga Prokopenko

, Gudmar Thorleifsson, Soren K. Thomsen, Jana K. Rundle, Lu Qi, E. M. Van Leeuwen, Benjamin F. Voight, M. Van De Bunt, R. M. Van Dam, Gunnar Sigurðsson, Heather M. Stringham, Michael Roden, Douglas Ruderfer

, Denis Rybin, Bengt Sennblad, Alena Stančáková, Gerald Steinbach, Petter Storm, Andrew R. Wood, Konstantin Strauch, Qi Sun, Barbara Thorand, Emmi Tikkanen, Anke Tonjes, Eleftheria Zeggini, Joseph Trakalo, Elena Tremoli, Tiinamaija Tuomi, Y. T. Van Der Schouw, G. Sigurosson, Roman Wennauer, Steven Wiltshire, Timo E. Saaristo, Eric Sijbrands, Unnur Thorsteinsdottir, Kari Stefansson, Michael Stumvoll, Scott Ra, C. Van Duijn, Juha Saltevo, Rainer Rauramaa, Veikko Salomaa, Jaakko Tuomilehto, Samuli Ripatti, Nicholas J. Wareham, Rob Sladek, Tanya M. Teslovich, Kyle J. Gaulton

, Teresa Ferreira, Yeji Lee, Reedik Maegi, Anubha Mahajan, Adam Locke

, Hans Kestler, Himanshu Chheda, Lewin Eisele, Reedik Mägi, Stefan Gustafsson, Harald Grallert, Lennart C. Karssen, Todd Green, Man Li, Mattias Frånberg, Han Chen, Christian Fuchsberger, Phoenix Kwan, Clement Ma, Gaulton Kj, Michael Linderman, Yingchang Lu, Nicola L. Beer, Matthias Blueher, Hyun Min Kang, Anil Chalisey, Gonçalo R. Abecasis, Peter Almgren, Damiano Baldassarre, Beverley Balkau, Rafn Benediktsson, Heiner Boeing, Erwin P. Bottinger, Lori Ll Bonnycastle, Noël P. Burtt, Jason Carey, Mattias Franberg, Guillaume Charpentier, Peter S. Chines, Marilyn C. Cornelis, David J. Couper, Andrew T. Crenshaw, Matthias Blüher, Alex Sf F. Doney, Mozhgan Dorkhan, Sarah Edkins, Johan G. Eriksson, Tonu Esko, Elodie Eury, João Fadista, Jason Flannick, Pierre Fontanillas, Caroline Fox, Karl Gertow, Christian Gieger

, Paul W. Franks, Bruna Gigante

, Clement, Omri Gottesman, Niels Grarup, Maija Hassinen, Christian Herder, George B. Grant, Reschen Me, Astradur B. Hreidarsson, Christopher J. Groves, Marit E. Jorgensen, Christian T. Have

, Torben Jorgensen, Oddgeir L. Holmen, Anna Jonsson, Steve E. Humphries, Leena Kinnunen, Norman Klopp, David J. Hunter, Augustine Kong, Peter Kovacs, Anne U. Jackson, Peter Kraft, Jasmina Kravic, Cordelia Langford, Wen-Hong L. Kao, Karin Leander

, Torben Jørgensen, Nicola D. Kerrison, Liming Liang, Peter Lichtner, Eero Lindholm, Allan Linneberg, Carl Gp P. Platou, Leena Peltonen, Stéphane Lobbens, Jian'an Luan, Valeriya Lyssenko, John Rb B. Perry, Olga McLeod, Julia Meyer, Cecilia M. Lindgren, Erwin P. Borringer, Evelin Mihailov, Ghazala Mirza, Marit E. Jørgensen, Ching-Ti Liu, Satu Männistö, Carmen Navarro, Nikolay Nn Oskolkov, Rayner Nw, Domenico Palli

, Martina Müller-Nurasyid, Satu Mannisto, Sonali Pechlivanis

, Markus Mm Nöthen, Katharine R. Owen, Thomas W. Muehleisen, Thomas W. Mühleisen, Martina Mueller-Nurasyid, Markus M. Noethen, Ian Dunham

, Ewan Birney, Lorenzo Pasquali, Jorge Ferrer, Josée Dupuis, Ruth Jf F. Loos, Eric Boerwinkle, Jose C. Florez, Nancy L. Pedersen, James S. Pankow, James B. Meigs, Satu Mӓnnistö, Frank B. Hu, Timo A. Lakka, Scott Lj, Lars Lind, Eeva Korpi-Hyövälti, Sirkka M. Keinanen Kiukaanniemi, Johanna Kuusisto, Markku Laakso, Andres Metspalu, Raimund Erbel, Susanne Moebus, Erik Ingelsson, Karl-Heinz Jöckel, Karl-Heinz Joecke, Richard N. Bergman, Bernhard O. Boehm, Francis S. Collins, Heikki Koistinen, Karen L. Mohlke, Kristian Hveem, Inger Njølstad, Annette Peters, Panagiotis Deloukas

, Peter J. Donnelly, U. De Faire, Karl-Heinz Jöcke, Timothy M. Frayling, Anders Hamsten, Andrew T. Hattersley, Oluf Pedersen, Thomas Illig, Stephane Cauchi, Philippe Froguel, Torben Hansen, Andrew D. Morris, Collin Na A. Palmer, Sekar Kathiresan, Olle Melander, Peter M. Nilsson, Leif C. Groop, Inês Barroso, Claudia Langenberg, Christopher A. O'Callaghan, Christopher A. O’Callaghan, Anna L. Gloyn, David Altshuler

, Michael Boehnke, Mark I. McCarthy, DIAbetes Genetics Replication And Meta-Analysis (Diagram) Consortium, Andrew P. Morris, A. DIAbet Genetics Replication Meta, Jackie Price

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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.

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

Abstract