The genetic architecture of type 2 diabetes

Fuchsberger, Christian, Flannick, Jason, Teslovich, Tanya M., Mahajan, Anubha, Agarwala, Vineeta, Gaulton, Kyle J., Ma, Clement, Fontanillas, Pierre, Moutsianas, Loukas, McCarthy, Davis J., Rivas, Manuel A., Perry, John R. B., Sim, Xueling, Blackwell, Thomas W., Robertson, Neil R., Rayner, N. William, Cingolani, Pablo, Locke, Adam E., Tajes, Juan Fernandez, Highland, Heather M., Dupuis, Josee, Chines, Peter S., Lindgren, Cecilia M., Hartl, Christopher, Jackson, Anne U., Chen, Han, Huyghe, Jeroen R., van de Bunt, Martijn, Pearson, Richard D., Kumar, Ashish, Mueller-Nurasyid, Martina, Grarup, Niels, Stringham, Heather M., Gamazon, Eric R., Lee, Jaehoon, Chen, Yuhui, Scott, Robert A., Below, Jennifer E., Chen, Peng, Huang, Jinyan, Go, Min Jin, Stitzel, Michael L., Pasko, Dorota, Parker, Stephen C. J., Varga, Tibor V., Green, Todd, Beer, Nicola L., Day-Williams, Aaron G., Ferreira, Teresa, Fingerlin, Tasha, Horikoshi, Momoko, Hu, Cheng, Huh, Iksoo, Ikram, Mohammad Kamran, Kim, Bong-Jo, Kim, Yongkang, Kim, Young Jin, Kwon, Min-Seok, Lee, Juyoung, Lee, Selyeong, Lin, Keng-Han, Maxwell, Taylor J., Nagai, Yoshihiko, Wang, Xu, Welch, Ryan P., Yoon, Joon, Zhang, Weihua, Barzilai, Nir, Voight, Benjamin F., Han, Bok-Ghee, Jenkinson, Christopher P., Kuulasmaa, Teemu, Kuusisto, Johanna, Manning, Alisa, Ng, Maggie C. Y., Palmer, Nicholette D., Balkau, Beverley, Stancakova, Alena, Abboud, Hanna E., Boeing, Heiner, Giedraitis, Vilmantas, Prabhakaran, Dorairaj, Gottesman, Omri, Scott, James, Carey, Jason, Kwan, Phoenix, Grant, George, Smith, Joshua D., Neale, Benjamin M., Purcell, Shaun, Butterworth, Adam S., Howson, Joanna M. M., Lee, Heung Man, Lu, Yingchang, Kwak, Soo-Heon, Zhao, Wei, Danesh, John, Lam, Vincent K. L., Park, Kyong Soo, Saleheen, Danish, So, Wing Yee, Tam, Claudia H. T., Afzal, Uzma, Aguilar, David, Arya, Rector, Aung, Tin, Chan, Edmund, Navarro, Carmen, Cheng, Ching-Yu, Palli, Domenico, Correa, Adolfo, Curran, Joanne E., Rybin, Denis, Farook, Vidya S., Fowler, Sharon P., Freedman, Barry I., Griswold, Michael, Hale, Daniel Esten, Hicks, Pamela J., Khor, Chiea-Chuen, Kumar, Satish, Lehne, Benjamin, Thuillier, Dorothee, Lim, Wei Yen, Liu, Jianjun, van der Schouw, Yvonne T., Loh, Marie, Musani, Solomon K., Puppala, Sobha, Scott, William R., Yengo, Loic, Tan, Sian-Tsung, Taylor, Herman A., Jr., Thameem, Farook, Wilson, Gregory, Sr., Wong, Tien Yin, Njolstad, Pal Rasmus, Levy, Jonathan C., Mangino, Massimo, Bonnycastle, Lori L., Schwarzmayr, Thomas, Fadista, Joao, Surdulescu, Gabriela L., Herder, Christian, Groves, Christopher J., Wieland, Thomas, Bork-Jensen, Jette, Brandslund, Ivan, Christensen, Cramer, Koistinen, Heikki A., Doney, Alex S. F., Kinnunen, Leena, Esko, Tonu, Farmer, Andrew J., Hakaste, Liisa, Hodgkiss, Dylan, Kravic, Jasmina, Lyssenko, Valeriya, Hollensted, Mette, Jorgensen, Marit E., Jorgensen, Torben, Ladenvall, Claes, Justesen, Johanne Marie, Karajamaki, Annemari, Kriebel, Jennifer, Rathmann, Wolfgang, Lannfelt, Lars, Lauritzen, Torsten, Narisu, Narisu, Linneberg, Allan, Melander, Olle, Milani, Lili, Neville, Matt, Orho-Melander, Marju, Qi, Lu, Qi, Qibin, Roden, Michael, Rolandsson, Olov, Swift, Amy, Rosengren, Anders H., Stirrups, Kathleen, Wood, Andrew R., Mihailov, Evelin, Blancher, Christine, Carneiro, Mauricio O., Maguire, Jared, Poplin, Ryan, Shakir, Khalid, Fennell, Timothy, DePristo, Mark, de Angelis, Martin Hrabe, Deloukas, Panos, Gjesing, Anette P., Jun, Goo, Nilsson, Peter, Murphy, Jacquelyn, Onofrio, Robert, Thorand, Barbara, Hansen, Torben, Meisinger, Christa, Hu, Frank B., Isomaa, Bo, Karpe, Fredrik, Liang, Liming, Peters, Annette, Huth, Cornelia, O'Rahilly, Stephen P., Palmer, Colin N. A., Pedersen, Oluf, Rauramaa, Rainer, Tuomilehto, Jaakko, Salomaa, Veikko, Watanabe, Richard M., Syvanen, Ann-Christine, Bergman, Richard N., Bharadwaj, Dwaipayan, Bottinger, Erwin P., Cho, Yoon Shin, Chandak, Giriraj R., Chan, Juliana C. N., Chia, Kee Seng, Daly, Mark J., Ebrahim, Shah B., Langenberg, Claudia, Elliott, Paul, Jablonski, Kathleen A., Lehman, Donna M., Jia, Weiping, Ma, Ronald C. W., Pollin, Toni I., Sandhu, Manjinder, Tandon, Nikhil, Froguel, Philippe, Barroso, Ines, Teo, Yik Ying, Zeggini, Eleftheria, Loos, Ruth J. F., Small, Kerrin S., Ried, Janina S., DeFronzo, Ralph A., Grallert, Harald, Glaser, Benjamin, Metspalu, Andres, Wareham, Nicholas J., Walker, Mark, Banks, Eric, Gieger, Christian, Ingelsson, Erik, Im, Hae Kyung, Illig, Thomas, Franks, Paul W., Buck, Gemma, Trakalo, Joseph, Buck, David, Prokopenko, Inga, Magi, Reedik, Lind, Lars, Farjoun, Yossi, Owen, Katharine R., Gloyn, Anna L., Strauch, Konstantin, Tuomi, Tiinamaija, Kooner, Jaspal Singh, Lee, Jong-Young, Park, Taesung, Donnelly, Peter, Morris, Andrew D., Hattersley, Andrew T., Bowden, Donald W., Collins, Francis S., Atzmon, Gil, Chambers, John C., Spector, Timothy D., Laakso, Markku, Strom, Tim M., Bell, Graeme I., Blangero, John, Duggirala, Ravindranath, Tai, E. Shyong, McVean, Gilean, Hanis, Craig L., Wilson, James G., Seielstad, Mark, Frayling, Timothy M., Meigs, James B., Cox, Nancy J., Sladek, Rob, Lander, Eric S., Gabriel, Stacey, Burtt, Noel P., Mohlke, Karen L., Meitinger, Thomas, Groop, Leif, Abecasis, Goncalo, Florez, Jose C., Scott, Laura J., Morris, Andrew P., Kang, Hyun Min, Boehnke, Michael, Altshuler, David and McCarthy, Mark I. (2016) The genetic architecture of type 2 diabetes. Nature, 536 7614: 41-47. doi:10.1038/nature18642


Author Fuchsberger, Christian
Flannick, Jason
Teslovich, Tanya M.
Mahajan, Anubha
Agarwala, Vineeta
Gaulton, Kyle J.
Ma, Clement
Fontanillas, Pierre
Moutsianas, Loukas
McCarthy, Davis J.
Rivas, Manuel A.
Perry, John R. B.
Sim, Xueling
Blackwell, Thomas W.
Robertson, Neil R.
Rayner, N. William
Cingolani, Pablo
Locke, Adam E.
Tajes, Juan Fernandez
Highland, Heather M.
Dupuis, Josee
Chines, Peter S.
Lindgren, Cecilia M.
Hartl, Christopher
Jackson, Anne U.
Chen, Han
Huyghe, Jeroen R.
van de Bunt, Martijn
Pearson, Richard D.
Kumar, Ashish
Mueller-Nurasyid, Martina
Grarup, Niels
Stringham, Heather M.
Gamazon, Eric R.
Lee, Jaehoon
Chen, Yuhui
Scott, Robert A.
Below, Jennifer E.
Chen, Peng
Huang, Jinyan
Go, Min Jin
Stitzel, Michael L.
Pasko, Dorota
Parker, Stephen C. J.
Varga, Tibor V.
Green, Todd
Beer, Nicola L.
Day-Williams, Aaron G.
Ferreira, Teresa
Fingerlin, Tasha
Horikoshi, Momoko
Hu, Cheng
Huh, Iksoo
Ikram, Mohammad Kamran
Kim, Bong-Jo
Kim, Yongkang
Kim, Young Jin
Kwon, Min-Seok
Lee, Juyoung
Lee, Selyeong
Lin, Keng-Han
Maxwell, Taylor J.
Nagai, Yoshihiko
Wang, Xu
Welch, Ryan P.
Yoon, Joon
Zhang, Weihua
Barzilai, Nir
Voight, Benjamin F.
Han, Bok-Ghee
Jenkinson, Christopher P.
Kuulasmaa, Teemu
Kuusisto, Johanna
Manning, Alisa
Ng, Maggie C. Y.
Palmer, Nicholette D.
Balkau, Beverley
Stancakova, Alena
Abboud, Hanna E.
Boeing, Heiner
Giedraitis, Vilmantas
Prabhakaran, Dorairaj
Gottesman, Omri
Scott, James
Carey, Jason
Kwan, Phoenix
Grant, George
Smith, Joshua D.
Neale, Benjamin M.
Purcell, Shaun
Butterworth, Adam S.
Howson, Joanna M. M.
Lee, Heung Man
Lu, Yingchang
Kwak, Soo-Heon
Zhao, Wei
Danesh, John
Lam, Vincent K. L.
Park, Kyong Soo
Saleheen, Danish
So, Wing Yee
Tam, Claudia H. T.
Afzal, Uzma
Aguilar, David
Arya, Rector
Aung, Tin
Chan, Edmund
Navarro, Carmen
Cheng, Ching-Yu
Palli, Domenico
Correa, Adolfo
Curran, Joanne E.
Rybin, Denis
Farook, Vidya S.
Fowler, Sharon P.
Freedman, Barry I.
Griswold, Michael
Hale, Daniel Esten
Hicks, Pamela J.
Khor, Chiea-Chuen
Kumar, Satish
Lehne, Benjamin
Thuillier, Dorothee
Lim, Wei Yen
Liu, Jianjun
van der Schouw, Yvonne T.
Loh, Marie
Musani, Solomon K.
Puppala, Sobha
Scott, William R.
Yengo, Loic
Tan, Sian-Tsung
Taylor, Herman A., Jr.
Thameem, Farook
Wilson, Gregory, Sr.
Wong, Tien Yin
Njolstad, Pal Rasmus
Levy, Jonathan C.
Mangino, Massimo
Bonnycastle, Lori L.
Schwarzmayr, Thomas
Fadista, Joao
Surdulescu, Gabriela L.
Herder, Christian
Groves, Christopher J.
Wieland, Thomas
Bork-Jensen, Jette
Brandslund, Ivan
Christensen, Cramer
Koistinen, Heikki A.
Doney, Alex S. F.
Kinnunen, Leena
Esko, Tonu
Farmer, Andrew J.
Hakaste, Liisa
Hodgkiss, Dylan
Kravic, Jasmina
Lyssenko, Valeriya
Hollensted, Mette
Jorgensen, Marit E.
Jorgensen, Torben
Ladenvall, Claes
Justesen, Johanne Marie
Karajamaki, Annemari
Kriebel, Jennifer
Rathmann, Wolfgang
Lannfelt, Lars
Lauritzen, Torsten
Narisu, Narisu
Linneberg, Allan
Melander, Olle
Milani, Lili
Neville, Matt
Orho-Melander, Marju
Qi, Lu
Qi, Qibin
Roden, Michael
Rolandsson, Olov
Swift, Amy
Rosengren, Anders H.
Stirrups, Kathleen
Wood, Andrew R.
Mihailov, Evelin
Blancher, Christine
Carneiro, Mauricio O.
Maguire, Jared
Poplin, Ryan
Shakir, Khalid
Fennell, Timothy
DePristo, Mark
de Angelis, Martin Hrabe
Deloukas, Panos
Gjesing, Anette P.
Jun, Goo
Nilsson, Peter
Murphy, Jacquelyn
Onofrio, Robert
Thorand, Barbara
Hansen, Torben
Meisinger, Christa
Hu, Frank B.
Isomaa, Bo
Karpe, Fredrik
Liang, Liming
Peters, Annette
Huth, Cornelia
O'Rahilly, Stephen P.
Palmer, Colin N. A.
Pedersen, Oluf
Rauramaa, Rainer
Tuomilehto, Jaakko
Salomaa, Veikko
Watanabe, Richard M.
Syvanen, Ann-Christine
Bergman, Richard N.
Bharadwaj, Dwaipayan
Bottinger, Erwin P.
Cho, Yoon Shin
Chandak, Giriraj R.
Chan, Juliana C. N.
Chia, Kee Seng
Daly, Mark J.
Ebrahim, Shah B.
Langenberg, Claudia
Elliott, Paul
Jablonski, Kathleen A.
Lehman, Donna M.
Jia, Weiping
Ma, Ronald C. W.
Pollin, Toni I.
Sandhu, Manjinder
Tandon, Nikhil
Froguel, Philippe
Barroso, Ines
Teo, Yik Ying
Zeggini, Eleftheria
Loos, Ruth J. F.
Small, Kerrin S.
Ried, Janina S.
DeFronzo, Ralph A.
Grallert, Harald
Glaser, Benjamin
Metspalu, Andres
Wareham, Nicholas J.
Walker, Mark
Banks, Eric
Gieger, Christian
Ingelsson, Erik
Im, Hae Kyung
Illig, Thomas
Franks, Paul W.
Buck, Gemma
Trakalo, Joseph
Buck, David
Prokopenko, Inga
Magi, Reedik
Lind, Lars
Farjoun, Yossi
Owen, Katharine R.
Gloyn, Anna L.
Strauch, Konstantin
Tuomi, Tiinamaija
Kooner, Jaspal Singh
Lee, Jong-Young
Park, Taesung
Donnelly, Peter
Morris, Andrew D.
Hattersley, Andrew T.
Bowden, Donald W.
Collins, Francis S.
Atzmon, Gil
Chambers, John C.
Spector, Timothy D.
Laakso, Markku
Strom, Tim M.
Bell, Graeme I.
Blangero, John
Duggirala, Ravindranath
Tai, E. Shyong
McVean, Gilean
Hanis, Craig L.
Wilson, James G.
Seielstad, Mark
Frayling, Timothy M.
Meigs, James B.
Cox, Nancy J.
Sladek, Rob
Lander, Eric S.
Gabriel, Stacey
Burtt, Noel P.
Mohlke, Karen L.
Meitinger, Thomas
Groop, Leif
Abecasis, Goncalo
Florez, Jose C.
Scott, Laura J.
Morris, Andrew P.
Kang, Hyun Min
Boehnke, Michael
Altshuler, David
McCarthy, Mark I.
Title The genetic architecture of type 2 diabetes
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
0028-0836
Publication date 2016-07-01
Year available 2016
Sub-type Article (original research)
DOI 10.1038/nature18642
Open Access Status Not yet assessed
Volume 536
Issue 7614
Start page 41
End page 47
Total pages 7
Publisher Nature Publishing Group
Language eng
Formatted abstract
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

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Sub-type: Article (original research)
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