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

Published

Journal Article

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 (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 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 (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

Full Text

Duke Authors

Cited Authors

  • Wessel, J; Chu, AY; Willems, SM; Wang, S; Yaghootkar, H; Brody, JA; Dauriz, M; Hivert, M-F; Raghavan, S; Lipovich, L; Hidalgo, B; Fox, K; Huffman, JE; An, P; Lu, Y; Rasmussen-Torvik, LJ; Grarup, N; Ehm, MG; Li, L; Baldridge, AS; StanĨáková, A; Abrol, R; Besse, C; Boland, A; Bork-Jensen, J; Fornage, M; Freitag, DF; Garcia, ME; Guo, X; Hara, K; Isaacs, A; Jakobsdottir, J; Lange, LA; Layton, JC; Li, M; Hua Zhao, J; 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, Y; Chen, Y-D; Cheng, C-Y; Correa, A; Czajkowski, J; Dehghan, A; Ehret, GB; Eiriksdottir, G; Escher, SA; Farmaki, A-E; Frånberg, 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; Jørgensen, ME; Jørgensen, T; Karaleftheri, M; Khor, CC; Kirkpatrick, A; Kraja, AT; Kuusisto, J; Lange, EM; Lee, IT; Lee, W-J; Leong, A; Liao, J; Liu, C; Liu, Y; 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; Renström, 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, WH-H; 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, J-H; 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; EPIC-InterAct Consortium, ; 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

Published Date

  • January 29, 2015

Published In

Volume / Issue

  • 6 /

Start / End Page

  • 5897 -

PubMed ID

  • 25631608

Pubmed Central ID

  • 25631608

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms6897

Language

  • eng