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

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

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Abstract

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.
Original languageEnglish
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015

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