Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | 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, N Rayner, W, Cingolani, P, Locke, AE, Tajes, JFernandez, 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, MJin, 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, MKamran, Kim, B-J, Kim, Y, Kim, YJin, 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, C Y Ng, M, 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, HMan, Lu, Y, Kwak, S-H, Zhao, W, Danesh, J, Lam, VKL, Park, KSoo, Saleheen, D, So, WYee, 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, DEsten, Hicks, PJ, Khor, C-C, Kumar, S, Lehne, B, Thuillier, D, Lim, WYen, 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, TYin, Njølstad, PRasmus, 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, JMarie, Käräjämäki, AM, 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, MHrabé, 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, YShin, Chandak, GR, Chan, JCN, Chia, KSeng, 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, YYing, 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, HKyung, 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, JSingh, 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, E Tai, S, 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, HMin, Boehnke, M, Altshuler, D, McCarthy, MI |
Journal | Nature |
Volume | 536 |
Issue | 7614 |
Pages | 41-7 |
Date Published | 2016 08 04 |
ISSN | 1476-4687 |
Keywords | Alleles, Diabetes Mellitus, Type 2, DNA Mutational Analysis, Europe, Exome, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, Humans, Sample Size |
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. |
DOI | 10.1038/nature18642 |
Pubmed | |
Alternate Journal | Nature |
PubMed ID | 27398621 |
PubMed Central ID | PMC5034897 |
Grant List | R01 DK093757 / DK / NIDDK NIH HHS / United States U01 DK085501 / DK / NIDDK NIH HHS / United States U01 HG005773 / HG / NHGRI NIH HHS / United States 095552 / / Wellcome Trust / United Kingdom R01 AG042188 / AG / NIA NIH HHS / United States K12CA139160 / CA / NCI NIH HHS / United States P60DK20595 / DK / NIDDK NIH HHS / United States U01DK085501 / DK / NIDDK NIH HHS / United States HHSN268201300046C / / PHS HHS / International DK093757 / DK / NIDDK NIH HHS / United States R00 DK092251 / DK / NIDDK NIH HHS / United States R00 DK099240 / DK / NIDDK NIH HHS / United States 1RC2DK088389 / DK / NIDDK NIH HHS / United States 090532 / / Wellcome Trust / United Kingdom U54 MD007588 / MD / NIMHD NIH HHS / United States R01 AG046949 / AG / NIA NIH HHS / United States MR/K002414/1 / / Medical Research Council / United Kingdom U54 HG003067 / HG / NHGRI NIH HHS / United States U01 DK085524 / DK / NIDDK NIH HHS / United States K24DK080140 / DK / NIDDK NIH HHS / United States DK085524 / DK / NIDDK NIH HHS / United States R01DK066358 / DK / NIDDK NIH HHS / United States U01 DK085545 / DK / NIDDK NIH HHS / United States 100956 / / Wellcome Trust / United Kingdom R01 DK106236 / DK / NIDDK NIH HHS / United States SP/04/002 / / British Heart Foundation / United Kingdom P01AG027734 / AG / NIA NIH HHS / United States R01 DK098032 / DK / NIDDK NIH HHS / United States U01DK085526 / DK / NIDDK NIH HHS / United States R01 DK072193 / DK / NIDDK NIH HHS / United States G0700931 / / Medical Research Council / United Kingdom SP/09/002 / / British Heart Foundation / United Kingdom U54HG003067 / HG / NHGRI NIH HHS / United States HHSN268201300048C / HL / NHLBI NIH HHS / United States MC_UU_12012/5 / / Medical Research Council / United Kingdom 098017 / / Wellcome Trust / United Kingdom T32 GM007753 / GM / NIGMS NIH HHS / United States R01MH090937 / MH / NIMH NIH HHS / United States MR/L01341X/1 / / Medical Research Council / United Kingdom 095101 / / Wellcome Trust / United Kingdom R01DK062370 / DK / NIDDK NIH HHS / United States MC_UU_12015/1 / / Medical Research Council / United Kingdom 084723 / / Wellcome Trust / United Kingdom 092447 / / Wellcome Trust / United Kingdom R01 DK101478 / DK / NIDDK NIH HHS / United States R01 HL102830 / HL / NHLBI NIH HHS / United States DK072193 / DK / NIDDK NIH HHS / United States R01 DK073541 / DK / NIDDK NIH HHS / United States P30AG038072 / AG / NIA NIH HHS / United States HHSN268201300049C / HL / NHLBI NIH HHS / United States R01 DK066358 / DK / NIDDK NIH HHS / United States / / CIHR / Canada 085475 / / Wellcome Trust / United Kingdom 064890 / / Wellcome Trust / United Kingdom 086596 / / Wellcome Trust / United Kingdom R01MH101820 / MH / NIMH NIH HHS / United States G0900747-‐91070 / / Medical Research Council / United Kingdom RC2 DK088389 / DK / NIDDK NIH HHS / United States P30DK020595 / DK / NIDDK NIH HHS / United States K24 DK080140 / DK / NIDDK NIH HHS / United States R01DK098032 / DK / NIDDK NIH HHS / United States HHSN268201300049C / / PHS HHS / International HHSN268201300047C / HL / NHLBI NIH HHS / United States U01 DK085526 / DK / NIDDK NIH HHS / United States RC2DK088389 / DK / NIDDK NIH HHS / United States R00DK092251 / DK / NIDDK NIH HHS / United States HHSN268201300050C / HL / NHLBI NIH HHS / United States 090367 / / Wellcome Trust / United Kingdom 098051 / / Wellcome Trust / United Kingdom U01 DK085584 / DK / NIDDK NIH HHS / United States DK085584 / DK / NIDDK NIH HHS / United States DK085545 / DK / NIDDK NIH HHS / United States G0601966 / / Medical Research Council / United Kingdom P01 AG027734 / AG / NIA NIH HHS / United States U01 DK078616 / DK / NIDDK NIH HHS / United States DK088389 / DK / NIDDK NIH HHS / United States DK085526 / DK / NIDDK NIH HHS / United States DK098032 / DK / NIDDK NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States P30 AG038072 / AG / NIA NIH HHS / United States 1R01AG042188 / AG / NIA NIH HHS / United States DK085501 / DK / NIDDK NIH HHS / United States R01 MH101820 / MH / NIMH NIH HHS / United States U01HG005773 / HG / NHGRI NIH HHS / United States T32GM007753 / GM / NIGMS NIH HHS / United States 083948 / / Wellcome Trust / United Kingdom RG/14/5/30893 / / British Heart Foundation / United Kingdom HHSN268201300046C / HL / NHLBI NIH HHS / United States HHSN268201300047C / / PHS HHS / International 098381 / / Wellcome Trust / United Kingdom G0800270 / / Medical Research Council / United Kingdom R01DK073541 / DK / NIDDK NIH HHS / United States R01 MH090937 / MH / NIMH NIH HHS / United States R01AG046949 / AG / NIA NIH HHS / United States G0601261 / / Medical Research Council / United Kingdom RC2-‐DK088389 / DK / NIDDK NIH HHS / United States R01HL102830 / HL / NHLBI NIH HHS / United States P30 DK020595 / DK / NIDDK NIH HHS / United States HHSN268201300050C / / PHS HHS / International P60 DK020595 / DK / NIDDK NIH HHS / United States HHSN268201300048C / / PHS HHS / International |
Additional Materials |
Nature DOI:10.1038/nature18642
The genetic architecture of type 2 diabetes.
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