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Nature DOI:10.1038/nature18642

The genetic architecture of type 2 diabetes.

Publication TypeJournal Article
Year of Publication2016
AuthorsFuchsberger, 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
JournalNature
Volume536
Issue7614
Pages41-7
Date Published2016 08 04
ISSN1476-4687
KeywordsAlleles, 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.

DOI10.1038/nature18642
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27398621?dopt=Abstract

Alternate JournalNature
PubMed ID27398621
PubMed Central IDPMC5034897
Grant ListR01 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
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