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

Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Franberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I. and Morris, Andrew P. (2015) Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nature Genetics, 47 12: 1415-1425. doi:10.1038/ng.3437


Author Gaulton, Kyle J.
Ferreira, Teresa
Lee, Yeji
Raimondo, Anne
Maegi, Reedik
Reschen, Michael E.
Mahajan, Anubha
Locke, Adam
Rayner, N. William
Robertson, Neil
Scott, Robert A.
Prokopenko, Inga
Scott, Laura J.
Green, Todd
Sparso, Thomas
Thuillier, Dorothee
Yengo, Loic
Grallert, Harald
Wahl, Simone
Franberg, Mattias
Strawbridge, Rona J.
Kestler, Hans
Chheda, Himanshu
Eisele, Lewin
Gustafsson, Stefan
Steinthorsdottir, Valgerdur
Thorleifsson, Gudmar
Qi, Lu
Karssen, Lennart C.
van Leeuwen, Elisabeth M.
Willems, Sara M.
Li, Man
Chen, Han
Fuchsberger, Christian
Kwan, Phoenix
Ma, Clement
Linderman, Michael
Lu, Yingchang
Thomsen, Soren K.
Rundle, Jana K.
Beer, Nicola L.
van de Bunt, Martijn
Chalisey, Anil
Kang, Hyun Min
Voight, Benjamin F.
Abecasis, Goncalo R.
Almgren, Peter
Baldassarre, Damiano
Balkau, Beverley
Benediktsson, Rafn
Blueher, Matthias
Boeing, Heiner
Bonnycastle, Lori L.
Bottinger, Erwin P.
Burtt, Noel P.
Carey, Jason
Charpentier, Guillaume
Chines, Peter S.
Cornelis, Marilyn C.
Couper, David J.
Crenshaw, Andrew T.
van Dam, Rob M.
Doney, Alex S. F.
Dorkhan, Mozhgan
Edkins, Sarah
Eriksson, Johan G.
Esko, Tonu
Eury, Elodie
Fadista, Joao
Flannick, Jason
Fontanillas, Pierre
Fox, Caroline
Franks, Paul W.
Gertow, Karl
Gieger, Christian
Gigante, Bruna
Gottesman, Omri
Grant, George B.
Grarup, Niels
Groves, Christopher J.
Hassinen, Maija
Have, Christian T.
Herder, Christian
Holmen, Oddgeir L.
Hreidarsson, Astradur B.
Humphries, Steve E.
Hunter, David J.
Jackson, Anne U.
Jonsson, Anna
Jorgensen, Marit E.
Jorgensen, Torben
Kao, Wen-Hong L.
Kerrison, Nicola D.
Kinnunen, Leena
Klopp, Norman
Kong, Augustine
Kovacs, Peter
Kraft, Peter
Kravic, Jasmina
Langford, Cordelia
Leander, Karin
Liang, Liming
Lichtner, Peter
Lindgren, Cecilia M.
Lindholm, Eero
Linneberg, Allan
Liu, Ching-Ti
Lobbens, Stephane
Luan, Jian'an
Lyssenko, Valeriya
Mannisto, Satu
McLeod, Olga
Meyer, Julia
Mihailov, Evelin
Mirza, Ghazala
Muehleisen, Thomas W.
Mueller-Nurasyid, Martina
Navarro, Carmen
Noethen, Markus M.
Oskolkov, Nikolay N.
Owen, Katharine R.
Palli, Domenico
Pechlivanis, Sonali
Peltonen, Leena
Perry, John R. B.
Platou, Carl G. P.
Roden, Michael
Ruderfer, Douglas
Rybin, Denis
van der Schouw, Yvonne T.
Sennblad, Bengt
Sigurdsson, Gunnar
Stancakova, Alena
Steinbach, Gerald
Storm, Petter
Strauch, Konstantin
Stringham, Heather M.
Sun, Qi
Thorand, Barbara
Tikkanen, Emmi
Tonjes, Anke
Trakalo, Joseph
Tremoli, Elena
Tuomi, Tiinamaija
Wennauer, Roman
Wiltshire, Steven
Wood, Andrew R.
Zeggini, Eleftheria
Dunham, Ian
Birney, Ewan
Pasquali, Lorenzo
Ferrer, Jorge
Loos, Ruth J. F.
Dupuis, Josee
Florez, Jose C.
Boerwinkle, Eric
Pankow, James S.
van Duijn, Cornelia
Sijbrands, Eric
Meigs, James B.
Hu, Frank B.
Thorsteinsdottir, Unnur
Stefansson, Kari
Lakka, Timo A.
Rauramaa, Rainer
Stumvoll, Michael
Pedersen, Nancy L.
Lind, Lars
Keinanen-Kiukaanniemi, Sirkka M.
Korpi-Hyovalti, Eeva
Saaristo, Timo E.
Saltevo, Juha
Kuusisto, Johanna
Laakso, Markku
Metspalu, Andres
Erbel, Raimund
Joecke, Karl-Heinz
Moebus, Susanne
Ripatti, Samuli
Salomaa, Veikko
Ingelsson, Erik
Boehm, Bernhard O.
Bergman, Richard N.
Collins, Francis S.
Mohlke, Karen L.
Koistinen, Heikki
Tuomilehto, Jaakko
Hveem, Kristian
Njolstad, Inger
Deloukas, Panagiotis
Donnelly, Peter J.
Frayling, Timothy M.
Hattersley, Andrew T.
de Faire, Ulf
Hamsten, Anders
Illig, Thomas
Peters, Annette
Cauchi, Stephane
Sladek, Rob
Froguel, Philippe
Hansen, Torben
Pedersen, Oluf
Morris, Andrew D.
Palmer, Collin N. A.
Kathiresan, Sekar
Melander, Olle
Nilsson, Peter M.
Groop, Leif C.
Barroso, Ines
Langenberg, Claudia
Wareham, Nicholas J.
O'Callaghan, Christopher A.
Gloyn, Anna L.
Altshuler, David
Boehnke, Michael
Teslovich, Tanya M.
McCarthy, Mark I.
Morris, Andrew P.
Title Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
1061-4036
Publication date 2015-12-01
Year available 2015
Sub-type Article (original research)
DOI 10.1038/ng.3437
Open Access Status Not yet assessed
Volume 47
Issue 12
Start page 1415
End page 1425
Total pages 11
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 47 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 50 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sat, 04 Mar 2017, 01:00:43 EST by Web Cron on behalf of Learning and Research Services (UQ Library)