The genetic architecture of type 2 diabetes

Christian Fuchsberger, Jason Flannick, Tanya M. Teslovich, Anubha Mahajan, Vineeta Agarwala, Kyle J. Gaulton, Clement Ma, Pierre Fontanillas, Loukas Moutsianas, Davis J. McCarthy, Manuel A. Rivas, John R B Perry, Xueling Sim, Thomas W. Blackwell, Neil R. Robertson, N. William Rayner, Pablo Cingolani, Adam E. Locke, Juan Fernandez Tajes, Heather M. Highland & 281 others Josee Dupuis, Peter S. Chines, Cecilia M. Lindgren, Christopher Hartl, Anne U. Jackson, Han Chen, Jeroen R. Huyghe, Martijn Van De Bunt, Richard D. Pearson, Ashish Kumar, Martina Müller-Nurasyid, Niels Grarup, Heather M. Stringham, Eric R. Gamazon, Jaehoon Lee, Yuhui Chen, Robert A. Scott, Jennifer E. Below, Peng Chen, Jinyan Huang, Min Jin Go, Hanna E. Abboud, Dorota Pasko, Stephen C J Parker, Tibor V. Varga, Todd Green, Nicola L. Beer, Aaron G. Day-Williams, Teresa Ferreira, Tasha Fingerlin, Momoko Horikoshi, Cheng Hu, Iksoo Huh, Mohammad Kamran Ikram, Bong Jo Kim, Yongkang Kim, Young Jin Kim, Min Seok Kwon, Juyoung Lee, Selyeong Lee, Keng Han Lin, Taylor J. Maxwell, Yoshihiko Nagai, Xu Wang, Ryan P. Welch, Joon Yoon, Weihua Zhang, Nir Barzilai, Benjamin F. Voight, Bok Ghee Han, Christopher P. Jenkinson, Teemu Kuulasmaa, Johanna Kuusisto, Alisa Manning, Maggie C Y Ng, Nicholette D. Palmer, Beverley Balkau, Alena Stančáková, Hanna E. Abboud, Heiner Boeing, Vilmantas Giedraitis, Dorairaj Prabhakaran, Omri Gottesman, James Scott, Jason Carey, Phoenix Kwan, George Grant, Joshua D. Smith, Benjamin M. Neale, Shaun Purcell, Adam S. Butterworth, Joanna M M Howson, Heung Man Lee, Yingchang Lu, Soo Heon Kwak, Wei Zhao, John Danesh, Vincent K L Lam, Kyong Soo Park, Danish Saleheen, Wing Yee So, Claudia H T Tam, Uzma Afzal, David Aguilar, Rector Arya, Tin Aung, Edmund Chan, Carmen Navarro, Ching Yu Cheng, Domenico Palli, Adolfo Correa, Joanne E. Curran, Denis Rybin, Vidya S. Farook, Sharon P. Fowler, Barry I. Freedman, Michael Griswold, Daniel Esten Hale, Pamela J. Hicks, Chiea Chuen Khor, Satish Kumar, Benjamin Lehne, Dorothée Thuillier, Wei Yen Lim, Jianjun Liu, Yvonne T. Van Der Schouw, Marie Loh, Solomon K. Musani, Sobha Puppala, William R. Scott, Loic Yengo, Sian Tsung Tan, Herman A. Taylor, Farook Thameem, Gregory Wilson, Tien Yin Wong, Pal Rasmus Njolstad, Jonathan C. Levy, Massimo Mangino, Lori L. Bonnycastle, Thomas Schwarzmayr, Joao Fadista, Gabriela L. Surdulescu, Christian Herder, Christopher J. Groves, Thomas Wieland, Jette Bork-Jensen, Ivan Brandslund, Cramer Christensen, Heikki A. Koistinen, Alex S F Doney, Leena Kinnunen, Tonu Esko, Andrew J. Farmer, Liisa Hakaste, Dylan Hodgkiss, Jasmina Kravic, Valeriya Lyssenko, Mette Hollensted, Marit E. Jorgensen, Torben Jorgensen, Claes Ladenvall, Johanne Marie Justesen, Annemari Käräjämäki, Jennifer Kriebel, Wolfgang Rathmann, Lars Lannfelt, Torsten Lauritzen, Narisu Narisu, Allan Linneberg, Olle Melander, Lili Milani, Matt Neville, Marju Orho-Melander, Lu Qi, Qibin Qi, Michael Roden, Olov Rolandsson, Amy Swift, Anders H. Rosengren, Kathleen Stirrups, Andrew R. Wood, Evelin Mihailov, Christine Blancher, Mauricio O. Carneiro, Jared Maguire, Ryan Poplin, Khalid Shakir, Timothy Fennell, Mark DePristo, Martin Hrabé De Angelis, Panos Deloukas, Anette P. Gjesing, Goo Jun, Peter Nilsson, Jacquelyn Murphy, Robert Onofrio, Barbara Thorand, Torben Hansen, Christa Meisinger, Frank B. Hu, Bo Isomaa, Fredrik Karpe, Liming Liang, Annette Peters, Cornelia Huth, Stephen P. O'Rahilly, Colin N A Palmer, Oluf Pedersen, Rainer Rauramaa, Jaakko Tuomilehto, Veikko Salomaa, Richard M. Watanabe, Ann Christine Syvänen, Richard N. Bergman, Dwaipayan Bharadwaj, Erwin P. Bottinger, Yoon Shin Cho, Giriraj R. Chandak, Juliana C N Chan, Kee Seng Chia, Mark J. Daly, Shah B. Ebrahim, Claudia Langenberg, Paul Elliott, Kathleen A. Jablonski, Donna M Lehman, Weiping Jia, Ronald C W Ma, Toni I. Pollin, Manjinder Sandhu, Nikhil Tandon, Philippe Froguel, Ines Barroso, Yik Ying Teo, Eleftheria Zeggini, Ruth J F Loos, Kerrin S. Small, Janina S. Ried, Ralph A Defronzo, Harald Grallert, Benjamin Glaser, Andres Metspalu, Nicholas J. Wareham, Mark Walker, Eric Banks, Christian Gieger, Erik Ingelsson, Hae Kyung Im, Thomas Illig, Paul W. Franks, Gemma Buck, Joseph Trakalo, David Buck, Inga Prokopenko, Reedik Mägi, Lars Lind, Yossi Farjoun, Katharine R. Owen, Anna L. Gloyn, Konstantin Strauch, Tiinamaija Tuomi, Jaspal Singh Kooner, Jong Young Lee, Taesung Park, Peter Donnelly, Andrew D. Morris, Andrew T. Hattersley, Donald W. Bowden, Francis S. Collins, Gil Atzmon, John C. Chambers, Timothy D. Spector, Markku Laakso, Tim M. Strom, Graeme I. Bell, John Blangero, Ravindranath Duggirala, E. Shyong Tai, Gilean McVean, Craig L. Hanis, James G. Wilson, Mark Seielstad, Timothy M. Frayling, James B. Meigs, Nancy J. Cox, Rob Sladek, Eric S. Lander, Stacey Gabriel, Noël P. Burtt, Karen L. Mohlke, Thomas Meitinger, Leif Groop, Goncalo Abecasis, Jose C. Florez, Laura J. Scott, Andrew P. Morris, Hyun Min Kang, Michael Boehnke, David Altshuler, Mark I. McCarthy

Research output: Contribution to journalArticle

385 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)41-47
Number of pages7
JournalNature
Volume536
Issue number7614
DOIs
StatePublished - Jul 11 2016

Fingerprint

Type 2 Diabetes Mellitus
Genome-Wide Association Study
Exome
Sample Size
Alleles
Genome

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Fuchsberger, C., Flannick, J., Teslovich, T. M., Mahajan, A., Agarwala, V., Gaulton, K. J., ... McCarthy, M. I. (2016). The genetic architecture of type 2 diabetes. Nature, 536(7614), 41-47. https://doi.org/10.1038/nature18642

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; Müller-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; Abboud, Hanna E.; 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; Stančáková, 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, Dorothée; 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.; Thameem, Farook; Wilson, Gregory; 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; Käräjämäki, 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 Hrabé; 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.; Syvänen, 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; Mägi, 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, Noël 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.

In: Nature, Vol. 536, No. 7614, 11.07.2016, p. 41-47.

Research output: Contribution to journalArticle

Fuchsberger, C, Flannick, J, Teslovich, TM, Mahajan, A, Agarwala, V, Gaulton, KJ, Ma, C, Fontanillas, P, Moutsianas, L, McCarthy, DJ, Rivas, MA, Perry, JRB, Sim, X, Blackwell, TW, Robertson, NR, Rayner, NW, Cingolani, P, Locke, AE, Tajes, JF, Highland, HM, Dupuis, J, Chines, PS, Lindgren, CM, Hartl, C, Jackson, AU, Chen, H, Huyghe, JR, Van De Bunt, M, Pearson, RD, Kumar, A, Müller-Nurasyid, M, Grarup, N, Stringham, HM, Gamazon, ER, Lee, J, Chen, Y, Scott, RA, Below, JE, Chen, P, Huang, J, Go, MJ, Abboud, HE, Pasko, D, Parker, SCJ, Varga, TV, Green, T, Beer, NL, Day-Williams, AG, Ferreira, T, Fingerlin, T, Horikoshi, M, Hu, C, Huh, I, Ikram, MK, Kim, BJ, Kim, Y, Kim, YJ, Kwon, MS, Lee, J, Lee, S, Lin, KH, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, BG, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stančáková, A, Abboud, HE, Boeing, H, Giedraitis, V, Prabhakaran, D, Gottesman, O, Scott, J, Carey, J, Kwan, P, Grant, G, Smith, JD, Neale, BM, Purcell, S, Butterworth, AS, Howson, JMM, Lee, HM, Lu, Y, Kwak, SH, Zhao, W, Danesh, J, Lam, VKL, Park, KS, Saleheen, D, So, WY, Tam, CHT, Afzal, U, Aguilar, D, Arya, R, Aung, T, Chan, E, Navarro, C, Cheng, CY, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, CC, Kumar, S, Lehne, B, Thuillier, D, Lim, WY, Liu, J, Van Der Schouw, YT, Loh, M, Musani, SK, Puppala, S, Scott, WR, Yengo, L, Tan, ST, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njolstad, PR, Levy, JC, Mangino, M, Bonnycastle, LL, Schwarzmayr, T, Fadista, J, Surdulescu, GL, Herder, C, Groves, CJ, Wieland, T, Bork-Jensen, J, Brandslund, I, Christensen, C, Koistinen, HA, Doney, ASF, Kinnunen, L, Esko, T, Farmer, AJ, Hakaste, L, Hodgkiss, D, Kravic, J, Lyssenko, V, Hollensted, M, Jorgensen, ME, Jorgensen, T, Ladenvall, C, Justesen, JM, Käräjämäki, A, Kriebel, J, Rathmann, W, Lannfelt, L, Lauritzen, T, Narisu, N, Linneberg, A, Melander, O, Milani, L, Neville, M, Orho-Melander, M, Qi, L, Qi, Q, Roden, M, Rolandsson, O, Swift, A, Rosengren, AH, Stirrups, K, Wood, AR, Mihailov, E, Blancher, C, Carneiro, MO, Maguire, J, Poplin, R, Shakir, K, Fennell, T, DePristo, M, De Angelis, MH, Deloukas, P, Gjesing, AP, Jun, G, Nilsson, P, Murphy, J, Onofrio, R, Thorand, B, Hansen, T, Meisinger, C, Hu, FB, Isomaa, B, Karpe, F, Liang, L, Peters, A, Huth, C, O'Rahilly, SP, Palmer, CNA, Pedersen, O, Rauramaa, R, Tuomilehto, J, Salomaa, V, Watanabe, RM, Syvänen, AC, Bergman, RN, Bharadwaj, D, Bottinger, EP, Cho, YS, Chandak, GR, Chan, JCN, Chia, KS, Daly, MJ, Ebrahim, SB, Langenberg, C, Elliott, P, Jablonski, KA, Lehman, DM, Jia, W, Ma, RCW, Pollin, TI, Sandhu, M, Tandon, N, Froguel, P, Barroso, I, Teo, YY, Zeggini, E, Loos, RJF, Small, KS, Ried, JS, Defronzo, RA, Grallert, H, Glaser, B, Metspalu, A, Wareham, NJ, Walker, M, Banks, E, Gieger, C, Ingelsson, E, Im, HK, Illig, T, Franks, PW, Buck, G, Trakalo, J, Buck, D, Prokopenko, I, Mägi, R, Lind, L, Farjoun, Y, Owen, KR, Gloyn, AL, Strauch, K, Tuomi, T, Kooner, JS, Lee, JY, Park, T, Donnelly, P, Morris, AD, Hattersley, AT, Bowden, DW, Collins, FS, Atzmon, G, Chambers, JC, Spector, TD, Laakso, M, Strom, TM, Bell, GI, Blangero, J, Duggirala, R, Tai, ES, McVean, G, Hanis, CL, Wilson, JG, Seielstad, M, Frayling, TM, Meigs, JB, Cox, NJ, Sladek, R, Lander, ES, Gabriel, S, Burtt, NP, Mohlke, KL, Meitinger, T, Groop, L, Abecasis, G, Florez, JC, Scott, LJ, Morris, AP, Kang, HM, Boehnke, M, Altshuler, D & McCarthy, MI 2016, 'The genetic architecture of type 2 diabetes', Nature, vol. 536, no. 7614, pp. 41-47. https://doi.org/10.1038/nature18642
Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ et al. The genetic architecture of type 2 diabetes. Nature. 2016 Jul 11;536(7614):41-47. https://doi.org/10.1038/nature18642
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 ; Müller-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 ; Abboud, Hanna E. ; 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 ; Stančáková, 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, Dorothée ; 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. ; Thameem, Farook ; Wilson, Gregory ; 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 ; Käräjämäki, 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 Hrabé ; 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. ; Syvänen, 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 ; Mägi, 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, Noël 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. / The genetic architecture of type 2 diabetes. In: Nature. 2016 ; Vol. 536, No. 7614. pp. 41-47.
@article{1ed5d983c30e494e8cddcdb65330e3ef,
title = "The genetic architecture of type 2 diabetes",
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.",
author = "Christian Fuchsberger and Jason Flannick and Teslovich, {Tanya M.} and Anubha Mahajan and Vineeta Agarwala and Gaulton, {Kyle J.} and Clement Ma and Pierre Fontanillas and Loukas Moutsianas and McCarthy, {Davis J.} and Rivas, {Manuel A.} and Perry, {John R B} and Xueling Sim and Blackwell, {Thomas W.} and Robertson, {Neil R.} and Rayner, {N. William} and Pablo Cingolani and Locke, {Adam E.} and Tajes, {Juan Fernandez} and Highland, {Heather M.} and Josee Dupuis and Chines, {Peter S.} and Lindgren, {Cecilia M.} and Christopher Hartl and Jackson, {Anne U.} and Han Chen and Huyghe, {Jeroen R.} and {Van De Bunt}, Martijn and Pearson, {Richard D.} and Ashish Kumar and Martina M{\"u}ller-Nurasyid and Niels Grarup and Stringham, {Heather M.} and Gamazon, {Eric R.} and Jaehoon Lee and Yuhui Chen and Scott, {Robert A.} and Below, {Jennifer E.} and Peng Chen and Jinyan Huang and Go, {Min Jin} and Abboud, {Hanna E.} and Dorota Pasko and Parker, {Stephen C J} and Varga, {Tibor V.} and Todd Green and Beer, {Nicola L.} and Day-Williams, {Aaron G.} and Teresa Ferreira and Tasha Fingerlin and Momoko Horikoshi and Cheng Hu and Iksoo Huh and Ikram, {Mohammad Kamran} and Kim, {Bong Jo} and Yongkang Kim and Kim, {Young Jin} and Kwon, {Min Seok} and Juyoung Lee and Selyeong Lee and Lin, {Keng Han} and Maxwell, {Taylor J.} and Yoshihiko Nagai and Xu Wang and Welch, {Ryan P.} and Joon Yoon and Weihua Zhang and Nir Barzilai and Voight, {Benjamin F.} and Han, {Bok Ghee} and Jenkinson, {Christopher P.} and Teemu Kuulasmaa and Johanna Kuusisto and Alisa Manning and Ng, {Maggie C Y} and Palmer, {Nicholette D.} and Beverley Balkau and Alena Stanč{\'a}kov{\'a} and Abboud, {Hanna E.} and Heiner Boeing and Vilmantas Giedraitis and Dorairaj Prabhakaran and Omri Gottesman and James Scott and Jason Carey and Phoenix Kwan and George Grant and Smith, {Joshua D.} and Neale, {Benjamin M.} and Shaun Purcell and Butterworth, {Adam S.} and Howson, {Joanna M M} and Lee, {Heung Man} and Yingchang Lu and Kwak, {Soo Heon} and Wei Zhao and John Danesh and Lam, {Vincent K L} and Park, {Kyong Soo} and Danish Saleheen and So, {Wing Yee} and Tam, {Claudia H T} and Uzma Afzal and David Aguilar and Rector Arya and Tin Aung and Edmund Chan and Carmen Navarro and Cheng, {Ching Yu} and Domenico Palli and Adolfo Correa and Curran, {Joanne E.} and Denis Rybin and Farook, {Vidya S.} and Fowler, {Sharon P.} and Freedman, {Barry I.} and Michael Griswold and Hale, {Daniel Esten} and Hicks, {Pamela J.} and Khor, {Chiea Chuen} and Satish Kumar and Benjamin Lehne and Doroth{\'e}e Thuillier and Lim, {Wei Yen} and Jianjun Liu and {Van Der Schouw}, {Yvonne T.} and Marie Loh and Musani, {Solomon K.} and Sobha Puppala and Scott, {William R.} and Loic Yengo and Tan, {Sian Tsung} and Taylor, {Herman A.} and Farook Thameem and Gregory Wilson and Wong, {Tien Yin} and Njolstad, {Pal Rasmus} and Levy, {Jonathan C.} and Massimo Mangino and Bonnycastle, {Lori L.} and Thomas Schwarzmayr and Joao Fadista and Surdulescu, {Gabriela L.} and Christian Herder and Groves, {Christopher J.} and Thomas Wieland and Jette Bork-Jensen and Ivan Brandslund and Cramer Christensen and Koistinen, {Heikki A.} and Doney, {Alex S F} and Leena Kinnunen and Tonu Esko and Farmer, {Andrew J.} and Liisa Hakaste and Dylan Hodgkiss and Jasmina Kravic and Valeriya Lyssenko and Mette Hollensted and Jorgensen, {Marit E.} and Torben Jorgensen and Claes Ladenvall and Justesen, {Johanne Marie} and Annemari K{\"a}r{\"a}j{\"a}m{\"a}ki and Jennifer Kriebel and Wolfgang Rathmann and Lars Lannfelt and Torsten Lauritzen and Narisu Narisu and Allan Linneberg and Olle Melander and Lili Milani and Matt Neville and Marju Orho-Melander and Lu Qi and Qibin Qi and Michael Roden and Olov Rolandsson and Amy Swift and Rosengren, {Anders H.} and Kathleen Stirrups and Wood, {Andrew R.} and Evelin Mihailov and Christine Blancher and Carneiro, {Mauricio O.} and Jared Maguire and Ryan Poplin and Khalid Shakir and Timothy Fennell and Mark DePristo and {De Angelis}, {Martin Hrab{\'e}} and Panos Deloukas and Gjesing, {Anette P.} and Goo Jun and Peter Nilsson and Jacquelyn Murphy and Robert Onofrio and Barbara Thorand and Torben Hansen and Christa Meisinger and Hu, {Frank B.} and Bo Isomaa and Fredrik Karpe and Liming Liang and Annette Peters and Cornelia Huth and O'Rahilly, {Stephen P.} and Palmer, {Colin N A} and Oluf Pedersen and Rainer Rauramaa and Jaakko Tuomilehto and Veikko Salomaa and Watanabe, {Richard M.} and Syv{\"a}nen, {Ann Christine} and Bergman, {Richard N.} and Dwaipayan Bharadwaj and Bottinger, {Erwin P.} and Cho, {Yoon Shin} and Chandak, {Giriraj R.} and Chan, {Juliana C N} and Chia, {Kee Seng} and Daly, {Mark J.} and Ebrahim, {Shah B.} and Claudia Langenberg and Paul Elliott and Jablonski, {Kathleen A.} and Lehman, {Donna M} and Weiping Jia and Ma, {Ronald C W} and Pollin, {Toni I.} and Manjinder Sandhu and Nikhil Tandon and Philippe Froguel and Ines Barroso and Teo, {Yik Ying} and Eleftheria Zeggini and Loos, {Ruth J F} and Small, {Kerrin S.} and Ried, {Janina S.} and Defronzo, {Ralph A} and Harald Grallert and Benjamin Glaser and Andres Metspalu and Wareham, {Nicholas J.} and Mark Walker and Eric Banks and Christian Gieger and Erik Ingelsson and Im, {Hae Kyung} and Thomas Illig and Franks, {Paul W.} and Gemma Buck and Joseph Trakalo and David Buck and Inga Prokopenko and Reedik M{\"a}gi and Lars Lind and Yossi Farjoun and Owen, {Katharine R.} and Gloyn, {Anna L.} and Konstantin Strauch and Tiinamaija Tuomi and Kooner, {Jaspal Singh} and Lee, {Jong Young} and Taesung Park and Peter Donnelly and Morris, {Andrew D.} and Hattersley, {Andrew T.} and Bowden, {Donald W.} and Collins, {Francis S.} and Gil Atzmon and Chambers, {John C.} and Spector, {Timothy D.} and Markku Laakso and Strom, {Tim M.} and Bell, {Graeme I.} and John Blangero and Ravindranath Duggirala and Tai, {E. Shyong} and Gilean McVean and Hanis, {Craig L.} and Wilson, {James G.} and Mark Seielstad and Frayling, {Timothy M.} and Meigs, {James B.} and Cox, {Nancy J.} and Rob Sladek and Lander, {Eric S.} and Stacey Gabriel and Burtt, {No{\"e}l P.} and Mohlke, {Karen L.} and Thomas Meitinger and Leif Groop and Goncalo Abecasis and Florez, {Jose C.} and Scott, {Laura J.} and Morris, {Andrew P.} and Kang, {Hyun Min} and Michael Boehnke and David Altshuler and McCarthy, {Mark I.}",
year = "2016",
month = "7",
day = "11",
doi = "10.1038/nature18642",
language = "English (US)",
volume = "536",
pages = "41--47",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7614",

}

TY - JOUR

T1 - The genetic architecture of type 2 diabetes

AU - Fuchsberger, Christian

AU - Flannick, Jason

AU - Teslovich, Tanya M.

AU - Mahajan, Anubha

AU - Agarwala, Vineeta

AU - Gaulton, Kyle J.

AU - Ma, Clement

AU - Fontanillas, Pierre

AU - Moutsianas, Loukas

AU - McCarthy, Davis J.

AU - Rivas, Manuel A.

AU - Perry, John R B

AU - Sim, Xueling

AU - Blackwell, Thomas W.

AU - Robertson, Neil R.

AU - Rayner, N. William

AU - Cingolani, Pablo

AU - Locke, Adam E.

AU - Tajes, Juan Fernandez

AU - Highland, Heather M.

AU - Dupuis, Josee

AU - Chines, Peter S.

AU - Lindgren, Cecilia M.

AU - Hartl, Christopher

AU - Jackson, Anne U.

AU - Chen, Han

AU - Huyghe, Jeroen R.

AU - Van De Bunt, Martijn

AU - Pearson, Richard D.

AU - Kumar, Ashish

AU - Müller-Nurasyid, Martina

AU - Grarup, Niels

AU - Stringham, Heather M.

AU - Gamazon, Eric R.

AU - Lee, Jaehoon

AU - Chen, Yuhui

AU - Scott, Robert A.

AU - Below, Jennifer E.

AU - Chen, Peng

AU - Huang, Jinyan

AU - Go, Min Jin

AU - Abboud, Hanna E.

AU - Pasko, Dorota

AU - Parker, Stephen C J

AU - Varga, Tibor V.

AU - Green, Todd

AU - Beer, Nicola L.

AU - Day-Williams, Aaron G.

AU - Ferreira, Teresa

AU - Fingerlin, Tasha

AU - Horikoshi, Momoko

AU - Hu, Cheng

AU - Huh, Iksoo

AU - Ikram, Mohammad Kamran

AU - Kim, Bong Jo

AU - Kim, Yongkang

AU - Kim, Young Jin

AU - Kwon, Min Seok

AU - Lee, Juyoung

AU - Lee, Selyeong

AU - Lin, Keng Han

AU - Maxwell, Taylor J.

AU - Nagai, Yoshihiko

AU - Wang, Xu

AU - Welch, Ryan P.

AU - Yoon, Joon

AU - Zhang, Weihua

AU - Barzilai, Nir

AU - Voight, Benjamin F.

AU - Han, Bok Ghee

AU - Jenkinson, Christopher P.

AU - Kuulasmaa, Teemu

AU - Kuusisto, Johanna

AU - Manning, Alisa

AU - Ng, Maggie C Y

AU - Palmer, Nicholette D.

AU - Balkau, Beverley

AU - Stančáková, Alena

AU - Abboud, Hanna E.

AU - Boeing, Heiner

AU - Giedraitis, Vilmantas

AU - Prabhakaran, Dorairaj

AU - Gottesman, Omri

AU - Scott, James

AU - Carey, Jason

AU - Kwan, Phoenix

AU - Grant, George

AU - Smith, Joshua D.

AU - Neale, Benjamin M.

AU - Purcell, Shaun

AU - Butterworth, Adam S.

AU - Howson, Joanna M M

AU - Lee, Heung Man

AU - Lu, Yingchang

AU - Kwak, Soo Heon

AU - Zhao, Wei

AU - Danesh, John

AU - Lam, Vincent K L

AU - Park, Kyong Soo

AU - Saleheen, Danish

AU - So, Wing Yee

AU - Tam, Claudia H T

AU - Afzal, Uzma

AU - Aguilar, David

AU - Arya, Rector

AU - Aung, Tin

AU - Chan, Edmund

AU - Navarro, Carmen

AU - Cheng, Ching Yu

AU - Palli, Domenico

AU - Correa, Adolfo

AU - Curran, Joanne E.

AU - Rybin, Denis

AU - Farook, Vidya S.

AU - Fowler, Sharon P.

AU - Freedman, Barry I.

AU - Griswold, Michael

AU - Hale, Daniel Esten

AU - Hicks, Pamela J.

AU - Khor, Chiea Chuen

AU - Kumar, Satish

AU - Lehne, Benjamin

AU - Thuillier, Dorothée

AU - Lim, Wei Yen

AU - Liu, Jianjun

AU - Van Der Schouw, Yvonne T.

AU - Loh, Marie

AU - Musani, Solomon K.

AU - Puppala, Sobha

AU - Scott, William R.

AU - Yengo, Loic

AU - Tan, Sian Tsung

AU - Taylor, Herman A.

AU - Thameem, Farook

AU - Wilson, Gregory

AU - Wong, Tien Yin

AU - Njolstad, Pal Rasmus

AU - Levy, Jonathan C.

AU - Mangino, Massimo

AU - Bonnycastle, Lori L.

AU - Schwarzmayr, Thomas

AU - Fadista, Joao

AU - Surdulescu, Gabriela L.

AU - Herder, Christian

AU - Groves, Christopher J.

AU - Wieland, Thomas

AU - Bork-Jensen, Jette

AU - Brandslund, Ivan

AU - Christensen, Cramer

AU - Koistinen, Heikki A.

AU - Doney, Alex S F

AU - Kinnunen, Leena

AU - Esko, Tonu

AU - Farmer, Andrew J.

AU - Hakaste, Liisa

AU - Hodgkiss, Dylan

AU - Kravic, Jasmina

AU - Lyssenko, Valeriya

AU - Hollensted, Mette

AU - Jorgensen, Marit E.

AU - Jorgensen, Torben

AU - Ladenvall, Claes

AU - Justesen, Johanne Marie

AU - Käräjämäki, Annemari

AU - Kriebel, Jennifer

AU - Rathmann, Wolfgang

AU - Lannfelt, Lars

AU - Lauritzen, Torsten

AU - Narisu, Narisu

AU - Linneberg, Allan

AU - Melander, Olle

AU - Milani, Lili

AU - Neville, Matt

AU - Orho-Melander, Marju

AU - Qi, Lu

AU - Qi, Qibin

AU - Roden, Michael

AU - Rolandsson, Olov

AU - Swift, Amy

AU - Rosengren, Anders H.

AU - Stirrups, Kathleen

AU - Wood, Andrew R.

AU - Mihailov, Evelin

AU - Blancher, Christine

AU - Carneiro, Mauricio O.

AU - Maguire, Jared

AU - Poplin, Ryan

AU - Shakir, Khalid

AU - Fennell, Timothy

AU - DePristo, Mark

AU - De Angelis, Martin Hrabé

AU - Deloukas, Panos

AU - Gjesing, Anette P.

AU - Jun, Goo

AU - Nilsson, Peter

AU - Murphy, Jacquelyn

AU - Onofrio, Robert

AU - Thorand, Barbara

AU - Hansen, Torben

AU - Meisinger, Christa

AU - Hu, Frank B.

AU - Isomaa, Bo

AU - Karpe, Fredrik

AU - Liang, Liming

AU - Peters, Annette

AU - Huth, Cornelia

AU - O'Rahilly, Stephen P.

AU - Palmer, Colin N A

AU - Pedersen, Oluf

AU - Rauramaa, Rainer

AU - Tuomilehto, Jaakko

AU - Salomaa, Veikko

AU - Watanabe, Richard M.

AU - Syvänen, Ann Christine

AU - Bergman, Richard N.

AU - Bharadwaj, Dwaipayan

AU - Bottinger, Erwin P.

AU - Cho, Yoon Shin

AU - Chandak, Giriraj R.

AU - Chan, Juliana C N

AU - Chia, Kee Seng

AU - Daly, Mark J.

AU - Ebrahim, Shah B.

AU - Langenberg, Claudia

AU - Elliott, Paul

AU - Jablonski, Kathleen A.

AU - Lehman, Donna M

AU - Jia, Weiping

AU - Ma, Ronald C W

AU - Pollin, Toni I.

AU - Sandhu, Manjinder

AU - Tandon, Nikhil

AU - Froguel, Philippe

AU - Barroso, Ines

AU - Teo, Yik Ying

AU - Zeggini, Eleftheria

AU - Loos, Ruth J F

AU - Small, Kerrin S.

AU - Ried, Janina S.

AU - Defronzo, Ralph A

AU - Grallert, Harald

AU - Glaser, Benjamin

AU - Metspalu, Andres

AU - Wareham, Nicholas J.

AU - Walker, Mark

AU - Banks, Eric

AU - Gieger, Christian

AU - Ingelsson, Erik

AU - Im, Hae Kyung

AU - Illig, Thomas

AU - Franks, Paul W.

AU - Buck, Gemma

AU - Trakalo, Joseph

AU - Buck, David

AU - Prokopenko, Inga

AU - Mägi, Reedik

AU - Lind, Lars

AU - Farjoun, Yossi

AU - Owen, Katharine R.

AU - Gloyn, Anna L.

AU - Strauch, Konstantin

AU - Tuomi, Tiinamaija

AU - Kooner, Jaspal Singh

AU - Lee, Jong Young

AU - Park, Taesung

AU - Donnelly, Peter

AU - Morris, Andrew D.

AU - Hattersley, Andrew T.

AU - Bowden, Donald W.

AU - Collins, Francis S.

AU - Atzmon, Gil

AU - Chambers, John C.

AU - Spector, Timothy D.

AU - Laakso, Markku

AU - Strom, Tim M.

AU - Bell, Graeme I.

AU - Blangero, John

AU - Duggirala, Ravindranath

AU - Tai, E. Shyong

AU - McVean, Gilean

AU - Hanis, Craig L.

AU - Wilson, James G.

AU - Seielstad, Mark

AU - Frayling, Timothy M.

AU - Meigs, James B.

AU - Cox, Nancy J.

AU - Sladek, Rob

AU - Lander, Eric S.

AU - Gabriel, Stacey

AU - Burtt, Noël P.

AU - Mohlke, Karen L.

AU - Meitinger, Thomas

AU - Groop, Leif

AU - Abecasis, Goncalo

AU - Florez, Jose C.

AU - Scott, Laura J.

AU - Morris, Andrew P.

AU - Kang, Hyun Min

AU - Boehnke, Michael

AU - Altshuler, David

AU - McCarthy, Mark I.

PY - 2016/7/11

Y1 - 2016/7/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84978128486&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978128486&partnerID=8YFLogxK

U2 - 10.1038/nature18642

DO - 10.1038/nature18642

M3 - Article

VL - 536

SP - 41

EP - 47

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7614

ER -