@article{3026698,
    title = "Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility",
    author = "Wessel, J. and Chu, A.Y. and Willems, S.M. and Wang, S. and Yaghootkar, H. and Brody, J.A. and Dauriz, M. and Hivert, M.-F. and Raghavan, S. and Lipovich, L. and Hidalgo, B. and Fox, K. and Huffman, J.E. and An, P. and Lu, Y. and Rasmussen-Torvik, L.J. and Grarup, N. and Ehm, M.G. and Li, L. and Baldridge, A.S. and Stančáková, A. and Abrol, R. and Besse, C. and Boland, A. and Bork-Jensen, J. and Fornage, M. and Freitag, D.F. and Garcia, M.E. and Guo, X. and Hara, K. and Isaacs, A. and Jakobsdottir, J. and Lange, L.A. and Layton, J.C. and Li, M. and Hua Zhao, J. and Meidtner, K. and Morrison, A.C. and Nalls, M.A. and Peters, M.J. and Sabater-Lleal, M. and Schurmann, C. and Silveira, A. and Smith, A.V. and Southam, L. and Stoiber, M.H. and Strawbridge, R.J. and Taylor, K.D. and Varga, T.V. and Allin, K.H. and Amin, N. and Aponte, J.L. and Aung, T. and Barbieri, C. and Bihlmeyer, N.A. and Boehnke, M. and Bombieri, C. and Bowden, D.W. and Burns, S.M. and Chen, Y. and Chen, Y.-D. and Cheng, C.-Y. and Correa, A. and Czajkowski, J. and Dehghan, A. and Ehret, G.B. and Eiriksdottir, G. and Escher, S.A. and Farmaki, A.-E. and Frånberg, M. and Gambaro, G. and Giulianini, F. and Goddard, W.A. and Goel, A. and Gottesman, O. and Grove, M.L. and Gustafsson, S. and Hai, Y. and Hallmans, G. and Heo, J. and Hoffmann, P. and Ikram, M.K. and Jensen, R.A. and Jørgensen, M.E. and Jørgensen, T. and Karaleftheri, M. and Khor, C.C. and Kirkpatrick, A. and Kraja, A.T. and Kuusisto, J. and Lange, E.M. and Lee, I.T. and Lee, W.-J. and Leong, A. and Liao, J. and Liu, C. and Liu, Y. and Lindgren, C.M. and Linneberg, A. and Malerba, G. and Mamakou, V. and Marouli, E. and Maruthur, N.M. and Matchan, A. and McKean-Cowdin, R. and McLeod, O. and Metcalf, G.A. and Mohlke, K.L. and Muzny, D.M. and Ntalla, I. and Palmer, N.D. and Pasko, D. and Peter, A. and Rayner, N.W. and Renström, F. and Rice, K. and Sala, C.F. and Sennblad, B. and Serafetinidis, I. and Smith, J.A. and Soranzo, N. and Speliotes, E.K. and Stahl, E.A. and Stirrups, K. and Tentolouris, N. and Thanopoulou, A. and Torres, M. and Traglia, M. and Tsafantakis, E. and Javad, S. and Yanek, L.R. and Zengini, E. and Becker, D.M. and Bis, J.C. and Brown, J.B. and Adrienne Cupples, L. and Hansen, T. and Ingelsson, E. and Karter, A.J. and Lorenzo, C. and Mathias, R.A. and Norris, J.M. and Peloso, G.M. and Sheu, W.H.-H. and Toniolo, D. and Vaidya, D. and Varma, R. and Wagenknecht, L.E. and Boeing, H. and Bottinger, E.P. and Dedoussis, G. and Deloukas, P. and Ferrannini, E. and Franco, O.H. and Franks, P.W. and Gibbs, R.A. and Gudnason, V. and Hamsten, A. and Harris, T.B. and Hattersley, A.T. and Hayward, C. and Hofman, A. and Jansson, J.-H. and Langenberg, C. and Launer, L.J. and Levy, D. and Oostra, B.A. and O'Donnell, C.J. and O'Rahilly, S. and Padmanabhan, S. and Pankow, J.S. and Polasek, O. and Province, M.A. and Rich, S.S. and Ridker, P.M. and Rudan, I. and Schulze, M.B. and Smith, B.H. and Uitterlinden, A.G. and Walker, M. and Watkins, H. and Wong, T.Y. and Zeggini, E. and Laakso, M. and Borecki, I.B. and Chasman, D.I. and Pedersen, O. and Psaty, B.M. and Shyong Tai, E. and Van Duijn, C.M. and Wareham, N.J. and Waterworth, D.M. and Boerwinkle, E. and Linda Kao, W.H. and Florez, J.C. and Loos, R.J.F. and Wilson, J.G. and Frayling, T.M. and Siscovick, D.S. and Dupuis, J. and Rotter, J.I. and Meigs, J.B. and Scott, R.A. and Goodarzi, M.O.",
    journal = "Nature Communications",
    year = "2015",
    volume = "6",
    publisher = "Nature Publishing Group",
    issn = "2041-1723",
    doi = "10.1038/ncomms6897",
    keywords = "glucose;  insulin;  long untranslated RNA;  G6PC2 protein, human;  GLP1R protein, human;  glucagon like peptide 1 receptor;  glucose 6 phosphatase;  glucose blood level;  insulin, diabetes;  frequency analysis;  gene expression;  genetic analysis;  genome;  genomics;  glucose, Article;  controlled study;  disease predisposition;  exome;  gene identification;  genetic association;  genetic code;  genetic variability;  human;  insulin release;  intron;  major clinical study;  non insulin dependent diabetes mellitus;  quantitative trait;  risk;  Black person;  blood;  Caucasian;  diet restriction;  DNA microarray;  exome;  gene locus;  genetic association study;  genetic predisposition;  genetic variation;  genetics;  glucose blood level;  metabolism;  mutation rate;  non insulin dependent diabetes mellitus;  single nucleotide polymorphism, African Continental Ancestry Group;  Blood Glucose;  Diabetes Mellitus, Type 2;  European Continental Ancestry Group;  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",
    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±0.01mmoll-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±0.035pmolinsulin mmolglucose-1, P=0.048), but higher 2-h glucose (β=0.16±0.05mmoll-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (p SKAT =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±0.004mmoll-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. © 2015 Macmillan Publishers Limited. All rights reserved."
}