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; 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; Michael L Stitzel; 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 Stancáková; 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; Loïc Yengo; Sian-Tsung Tan; Herman A Taylor; Farook Thameem; Gregory Wilson; Tien Yin Wong; Pål Rasmus Njølstad; Jonathan C Levy; Massimo Mangino; Lori L Bonnycastle; Thomas Schwarzmayr; João 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; Tõnu Esko; Andrew J Farmer; Liisa Hakaste; Dylan Hodgkiss; Jasmina Kravic; Valeriya Lyssenko; Mette Hollensted; Marit E Jørgensen; Torben Jørgensen; 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; Inês 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

doi:10.1038/nature18642

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 HighlandJosee 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, Michael L Stitzel, 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 Stancáková, 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, Loïc Yengo, Sian-Tsung Tan, Herman A Taylor, Farook Thameem, Gregory Wilson, Tien Yin Wong, Pål Rasmus Njølstad, Jonathan C Levy, Massimo Mangino, Lori L Bonnycastle, Thomas Schwarzmayr, João 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, Tõnu Esko, Andrew J Farmer, Liisa Hakaste, Dylan Hodgkiss, Jasmina Kravic, Valeriya Lyssenko, Mette Hollensted, Marit E Jørgensen, Torben Jørgensen, 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, Inês 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

553 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	536
Udgave nummer	7614
Sider (fra-til)	41-47
Antal sider	7
ISSN	0028-0836
DOI	https://doi.org/10.1038/nature18642
Status	Udgivet - 11 jul. 2016

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Fuchsberger, C., Flannick, J., Teslovich, T. M., Mahajan, A., Agarwala, V., Gaulton, K. J., Ma, C., Fontanillas, P., Moutsianas, L., McCarthy, D. J., Rivas, M. A., Perry, J. R. B., Sim, X., Blackwell, T. W., Robertson, N. R., Rayner, N. W., Cingolani, P., Locke, A. E., Fernandez Tajes, J., ... McCarthy, M. I. (2016). The genetic architecture of type 2 diabetes. Nature, 536(7614), 41-47. https://doi.org/10.1038/nature18642

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, Fernandez Tajes, J, 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, Stitzel, ML, 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, B-J, Kim, Y, Kim, YJ, Kwon, M-S, Lee, J, Lee, S, Lin, K-H, Maxwell, TJ, Nagai, Y, Wang, X, Welch, RP, Yoon, J, Zhang, W, Barzilai, N, Voight, BF, Han, B-G, Jenkinson, CP, Kuulasmaa, T, Kuusisto, J, Manning, A, Ng, MCY, Palmer, ND, Balkau, B, Stancáková, 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, S-H, 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, C-Y, Palli, D, Correa, A, Curran, JE, Rybin, D, Farook, VS, Fowler, SP, Freedman, BI, Griswold, M, Hale, DE, Hicks, PJ, Khor, C-C, 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, S-T, Taylor, HA, Thameem, F, Wilson, G, Wong, TY, Njølstad, 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, Jørgensen, ME, Jørgensen, 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, Hrabé de Angelis, M, 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, A-C, 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, J-Y, 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, bind 536, nr. 7614, s. 41-47. https://doi.org/10.1038/nature18642

@article{57403a3cf4394a618f957adfd361eee8,

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.",

keywords = "Alleles, DNA Mutational Analysis, Diabetes Mellitus, Type 2, Europe, Exome, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, Humans, Sample Size, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

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 {Fernandez Tajes}, Juan 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 Stitzel, {Michael L} 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 Bong-Jo Kim and Yongkang Kim and Kim, {Young Jin} and Min-Seok Kwon and Juyoung Lee and Selyeong Lee and Keng-Han Lin 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 Bok-Ghee Han 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 Stanc{\'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 Soo-Heon Kwak 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 Ching-Yu Cheng 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 Chiea-Chuen Khor 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 Lo{\"i}c Yengo and Sian-Tsung Tan and Taylor, {Herman A} and Farook Thameem and Gregory Wilson and Wong, {Tien Yin} and Nj{\o}lstad, {P{\aa}l Rasmus} and Levy, {Jonathan C} and Massimo Mangino and Bonnycastle, {Lori L} and Thomas Schwarzmayr and Jo{\~a}o 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 T{\~o}nu Esko and Farmer, {Andrew J} and Liisa Hakaste and Dylan Hodgkiss and Jasmina Kravic and Valeriya Lyssenko and Mette Hollensted and J{\o}rgensen, {Marit E} and Torben J{\o}rgensen 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 {Hrab{\'e} de Angelis}, Martin 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 Ann-Christine Syv{\"a}nen 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 In{\^e}s 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 Jong-Young Lee 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 = jul,

day = "11",

doi = "10.1038/nature18642",

language = "English",

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

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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.

KW - Alleles

KW - DNA Mutational Analysis

KW - Diabetes Mellitus, Type 2

KW - Europe

KW - Exome

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genotyping Techniques

KW - Humans

KW - Sample Size

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nature18642

DO - 10.1038/nature18642

M3 - Journal article

C2 - 27398621

SN - 0028-0836

VL - 536

SP - 41

EP - 47

JO - Nature

JF - Nature

IS - 7614

ER -

The genetic architecture of type 2 diabetes

Abstract

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