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The genetic architecture of type 2 diabetes

Lookup NU author(s): Professor Mark Walker

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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.


Publication metadata

Author(s): 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, Muller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen YH, 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 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, Stancakova 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 YC, 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, Karajamaki 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 QB, 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 LM, Peters A, Huth C, O'Rahilly SP, Palmer CNA, Pedersen O, Rauramaa R, Tuomilehto J, Salomaa V, Watanabe RM, Syvanen 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 WP, 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, Magi 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

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2016

Volume: 536

Issue: 7614

Pages: 41-70

Online publication date: 11/07/2016

Acceptance date: 12/06/2016

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nature18642

DOI: 10.1038/nature18642


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Funding

Funder referenceFunder name
Canadian Institutes of Health Research
064890Wellcome Trust
083948Wellcome Trust
085475Wellcome Trust
090532Wellcome Trust
092447Wellcome Trust
095101Wellcome Trust
098051Wellcome Trust
098381Wellcome Trust
084723Wellcome Trust
086596Wellcome Trust
090367Wellcome Trust
095552Wellcome Trust
098017Wellcome Trust
100956Wellcome Trust
1RC2DK088389NIDDK NIH HHS
1R01AG042188NIA NIH HHS
DK093757NIDDK NIH HHS
DK072193NIDDK NIH HHS
DK085501NIDDK NIH HHS
DK085524NIDDK NIH HHS
DK085526NIDDK NIH HHS
DK085545NIDDK NIH HHS
DK085584NIDDK NIH HHS
DK088389NIDDK NIH HHS
DK098032NIDDK NIH HHS
G0601261Medical Research Council
G0601966Medical Research Council
G0700931Medical Research Council
HHSN268201300049CPHS HHS
HHSN268201300049CNHLBI NIH HHS
HHSN268201300050CNHLBI NIH HHS
HHSN268201300050CPHS HHS
G0800270Medical Research Council
G0900747-‐91070Medical Research Council
K24 DK080140NIDDK NIH HHS
HHSN268201300046CNHLBI NIH HHS
HHSN268201300046CPHS HHS
HHSN268201300047CPHS HHS
HHSN268201300047CNHLBI NIH HHS
HHSN268201300048CPHS HHS
HHSN268201300048CNHLBI NIH HHS
K12CA139160NCI NIH HHS
K24DK080140NIDDK NIH HHS
P30AG038072NIA NIH HHS
P60DK20595NIDDK NIH HHS
R00 DK092251NIDDK NIH HHS
R00 DK099240NIDDK NIH HHS
R00DK092251NIDDK NIH HHS
R01 DK066358NIDDK NIH HHS
R01 DK072193NIDDK NIH HHS
R01 DK073541NIDDK NIH HHS
R01 DK093757NIDDK NIH HHS
R01 HL102830NHLBI NIH HHS
R01 MH090937NIMH NIH HHS
R01 MH101820NIMH NIH HHS
R01DK062370NIDDK NIH HHS
R01DK073541NIDDK NIH HHS
R01MH090937NIMH NIH HHS
R01MH101820NIMH NIH HHS
RC2DK088389NIDDK NIH HHS
RC2-‐DK088389NIDDK NIH HHS
P01 AG027734NIA NIH HHS
P01AG027734NIA NIH HHS
P30 AG038072NIA NIH HHS
P30 DK020595NIDDK NIH HHS
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P60 DK020595NIDDK NIH HHS
SP/04/002British Heart Foundation
T32 GM007753NIGMS NIH HHS
U01 DK062370NIDDK NIH HHS
U01 DK078616NIDDK NIH HHS
U01 DK085545NIDDK NIH HHS
R01 AG042188NIA NIH HHS
R01 AG046949NIA NIH HHS
R01 DK098032NIDDK NIH HHS
R01 DK101478NIDDK NIH HHS
R01 DK106236NIDDK NIH HHS
U01DK085501NIDDK NIH HHS
U01DK085526NIDDK NIH HHS
U01HG005773NHGRI NIH HHS
U54 HG003067NHGRI NIH HHS
R01AG046949NIA NIH HHS
R01DK066358NIDDK NIH HHS
R01DK098032NIDDK NIH HHS
R01HL102830NHLBI NIH HHS
RC2 DK088389NIDDK NIH HHS
U54HG003067NHGRI NIH HHS
SP/09/002British Heart Foundation
T32GM007753NIGMS NIH HHS
U01 DK085501NIDDK NIH HHS
U01 DK085524NIDDK NIH HHS
U01 DK085526NIDDK NIH HHS
U01 DK085584NIDDK NIH HHS
U01 HG005773NHGRI NIH HHS
U54 MD007588NIMHD NIH HHS

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