Title | Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. |
Publication Type | Journal Article |
Year of Publication | 2015 |
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, Stančáková, 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, Zhao, JHua, 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-DI, 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, 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, L Cupples, A, 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, Laakso, M, Borecki, IB, Chasman, DI, Pedersen, O, Psaty, BM, E Tai, S, van Duijn, CM, Wareham, NJ, Waterworth, DM, Boerwinkle, E, Kao, WHLinda, Florez, JC, Loos, RJF, Wilson, JG, Frayling, TM, Siscovick, DS, Dupuis, J, Rotter, JI, Meigs, JB, Scott, RA, Goodarzi, MO |
Corporate Authors | EPIC-InterAct Consortium |
Journal | Nat Commun |
Volume | 6 |
Pagination | 5897 |
Date Published | 2015 Jan 29 |
ISSN | 2041-1723 |
Keywords | Black People, Blood Glucose, Diabetes Mellitus, Type 2, Exome, Fasting, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Glucagon-Like Peptide-1 Receptor, Glucose-6-Phosphatase, Humans, Insulin, Mutation Rate, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, White People |
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 (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. |
DOI | 10.1038/ncomms6897 |
Alternate Journal | Nat Commun |
PubMed ID | 25631608 |
PubMed Central ID | PMC4311266 |
Grant List | R01 DK093757 / DK / NIDDK NIH HHS / United States R01 DK078616 / DK / NIDDK NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States UL1RR025005 / RR / NCRR NIH HHS / United States HHSN268201100037C / HL / NHLBI NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States R01 HL071025 / HL / NHLBI NIH HHS / United States R01-HL-088215 / HL / NHLBI NIH HHS / United States R01 HL112064 / HL / NHLBI NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States DK081350 / DK / NIDDK NIH HHS / United States N01-HC-95162 / HC / NHLBI NIH HHS / United States G0600717 / MRC_ / Medical Research Council / United Kingdom HHSN268201100009I / HL / NHLBI NIH HHS / United States DK093757 / DK / NIDDK NIH HHS / United States HHSN268201300026C / HL / NHLBI NIH HHS / United States UL1TR000124 / TR / NCATS NIH HHS / United States N01AG12100 / AG / NIA NIH HHS / United States HG007112 / HG / NHGRI NIH HHS / United States N1AG62101A / AG / NIA NIH HHS / United States R56 DK062370 / DK / NIDDK NIH HHS / United States N01HC95160 / HL / NHLBI NIH HHS / United States HL59684 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States R01 HL087698 / HL / NHLBI NIH HHS / United States UL1-TR000124 / TR / NCATS NIH HHS / United States 5RC2HL102419 / HL / NHLBI NIH HHS / United States R01 HL071251 / HL / NHLBI NIH HHS / United States R00 DK081350 / DK / NIDDK NIH HHS / United States R01 HL107816 / HL / NHLBI NIH HHS / United States UL1 TR000150 / TR / NCATS NIH HHS / United States R01HL59367 / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States R01 HL071259 / HL / NHLBI NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States MC_UP_A100_1003 / MRC_ / Medical Research Council / United Kingdom R01 HG007112 / HG / NHGRI NIH HHS / United States N01 AG062101 / AG / NIA NIH HHS / United States HL47902 / HL / NHLBI NIH HHS / United States N01 HC095167 / HC / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States HL071025-01A1 / HL / NHLBI NIH HHS / United States MC_U106179471 / MRC_ / Medical Research Council / United Kingdom N01HC95163 / HL / NHLBI NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States EY14684 / EY / NEI NIH HHS / United States UL1 TR001079 / TR / NCATS NIH HHS / United States SP/04/002 / BHF_ / British Heart Foundation / United Kingdom HHSN268201100005G / HL / NHLBI NIH HHS / United States R01 HL071252 / HL / NHLBI NIH HHS / United States R01 HL059684-01A1 / HL / NHLBI NIH HHS / United States HHSN268201100008I / HL / NHLBI NIH HHS / United States 075491/Z/04 / WT_ / Wellcome Trust / United Kingdom R01 HL068986 / HL / NHLBI NIH HHS / United States R01 HL043851 / HL / NHLBI NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States HL047890 / HL / NHLBI NIH HHS / United States R01HL107816 / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States RR-024156 / RR / NCRR NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States N01-HC-95163 / HC / NHLBI NIH HHS / United States MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom N01-HC-95168 / HC / NHLBI NIH HHS / United States 4R00HG006698-03 / HG / NHGRI NIH HHS / United States N01HC95169 / HL / NHLBI NIH HHS / United States U01 HL120393 / HL / NHLBI NIH HHS / United States CZD/16/6 / CSO_ / Chief Scientist Office / United Kingdom R01 DK072193 / DK / NIDDK NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States R01 HL071250 / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States R01 HL086694 / HL / NHLBI NIH HHS / United States UL1 RR024156 / RR / NCRR NIH HHS / United States HL047887 / HL / NHLBI NIH HHS / United States N01-HC-95159 / HC / NHLBI NIH HHS / United States P30 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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.
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