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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Lookup NU author(s): Professor Mark Walker



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

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Author(s): Wessel J, Chu AY, Willems SM, Wang S, Yaghootkar H, Brody JA, Dauriz M, Hivert MF, Raghavan S, Lipovich L, Hidalgo B, Fox K, Huffman JE, An P, Lu YC, Rasmussen-Torvik LJ, Grarup N, Ehm MG, Li L, Baldridge AS, Stancakova A, Abrol R, Besse CL, Boland A, Bork-Jensen J, Fornage M, Freitag DF, Garcia ME, Guo XQ, Hara K, Isaacs A, Jakobsdottir J, Lange LA, Layton JC, Li M, Zhao JH, Meidtner K, Morrison AC, Nalls MA, Peters MJ, Sabater-Lleal M, Schurmann C, Silveira A, Smith AV, Southam L, Stoiber MH, Strawbridge RJ, Taylor KD, Varga TV, Allin KH, Amin N, Aponte JL, Aung T, Barbieri C, Bihlmeyer NA, Boehnke M, Bombieri C, Bowden DW, Burns SM, Chen YN, Chen YD, Cheng CY, Correa A, Czajkowski J, Dehghan A, Ehret GB, Eiriksdottir G, Escher SA, Farmaki AE, Franberg M, Gambaro G, Giulianini F, Goddard WA, Goel A, Gottesman O, Grove ML, Gustafsson S, Hai Y, Hallmans G, Heo J, Hoffmann P, Ikram MK, Jensen RA, Jorgensen ME, Jorgensen T, Karaleftheri M, Khor CC, Kirkpatrick A, Kraja AT, Kuusisto J, Lange EM, Lee IT, Lee WJ, Leong A, Liao JM, Liu CY, Liu YM, Lindgren CM, Linneberg A, Malerba G, Mamakou V, Marouli E, Maruthur NM, Matchan A, McKean-Cowdin R, McLeod O, Metcalf GA, Mohlke KL, Muzny DM, Ntalla I, Palmer ND, Pasko D, Peter A, Rayner NW, Renstrom F, Rice K, Sala CF, Sennblad B, Serafetinidis I, Smith JA, Soranzo N, Speliotes EK, Stahl EA, Stirrups K, Tentolouris N, Thanopoulou A, Torres M, Traglia M, Tsafantakis E, Javad S, Yanek LR, Zengini E, Becker DM, Bis JC, Brown JB, Cupples LA, Hansen T, Ingelsson E, Karter AJ, Lorenzo C, Mathias RA, Norris JM, Peloso GM, Sheu WHH, Toniolo D, Vaidya D, Varma R, Wagenknecht LE, Boeing H, Bottinger EP, Dedoussis G, Deloukas P, Ferrannini E, Franco OH, Franks PW, Gibbs RA, Gudnason V, Hamsten A, Harris TB, Hattersley AT, Hayward C, Hofman A, Jansson JH, Langenberg C, Launer LJ, Levy D, Oostra BA, O'Donnell CJ, O'Rahilly S, Padmanabhan S, Pankow JS, Polasek O, Province MA, Rich SS, Ridker PM, Rudan I, Schulze MB, Smith BH, Uitterlinden AG, Walker M, Watkins H, Wong TY, Zeggini E, Laakso M, Borecki IB, Chasman DI, Pedersen O, Psaty BM, Tai ES, van Duijn CM, Wareham NJ, Waterworth DM, Boerwinkle E, Kao WHL, Florez JC, Loos RJF, Wilson JG, Frayling TM, Siscovick DS, Dupuis J, Rotter JI, Meigs JB, Scott RA, Goodarzi MO, Sharp SJ, Forouhi NG, Kerrison ND, Lucarelli DM, Sims M, Barroso I, McCarthy MI, Arriola L, Balkau B, Barricarte A, Gonzalez C, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Rolandsson O, Sacerdote C, Sanchez MJ, Slimani N, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, Riboli E, The EPIC-InterAct Consortium

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2015

Volume: 6

Online publication date: 29/01/2015

Acceptance date: 12/11/2014

Date deposited: 07/04/2015

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/ncomms6897


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