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

Επιστημονική δημοσίευση - Άρθρο Περιοδικού uoadl:3026698 71 Αναγνώσεις

Μονάδα:
Ερευνητικό υλικό ΕΚΠΑ
Τίτλος:
Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Έτος δημοσίευσης:
2015
Συγγραφείς:
Wessel, J.
Chu, A.Y.
Willems, S.M.
Wang, S.
Yaghootkar, H.
Brody, J.A.
Dauriz, M.
Hivert, M.-F.
Raghavan, S.
Lipovich, L.
Hidalgo, B.
Fox, K.
Huffman, J.E.
An, P.
Lu, Y.
Rasmussen-Torvik, L.J.
Grarup, N.
Ehm, M.G.
Li, L.
Baldridge, A.S.
Stančáková, A.
Abrol, R.
Besse, C.
Boland, A.
Bork-Jensen, J.
Fornage, M.
Freitag, D.F.
Garcia, M.E.
Guo, X.
Hara, K.
Isaacs, A.
Jakobsdottir, J.
Lange, L.A.
Layton, J.C.
Li, M.
Hua Zhao, J.
Meidtner, K.
Morrison, A.C.
Nalls, M.A.
Peters, M.J.
Sabater-Lleal, M.
Schurmann, C.
Silveira, A.
Smith, A.V.
Southam, L.
Stoiber, M.H.
Strawbridge, R.J.
Taylor, K.D.
Varga, T.V.
Allin, K.H.
Amin, N.
Aponte, J.L.
Aung, T.
Barbieri, C.
Bihlmeyer, N.A.
Boehnke, M.
Bombieri, C.
Bowden, D.W.
Burns, S.M.
Chen, Y.
Chen, Y.-D.
Cheng, C.-Y.
Correa, A.
Czajkowski, J.
Dehghan, A.
Ehret, G.B.
Eiriksdottir, G.
Escher, S.A.
Farmaki, A.-E.
Frånberg, M.
Gambaro, G.
Giulianini, F.
Goddard, W.A.
Goel, A.
Gottesman, O.
Grove, M.L.
Gustafsson, S.
Hai, Y.
Hallmans, G.
Heo, J.
Hoffmann, P.
Ikram, M.K.
Jensen, R.A.
Jørgensen, M.E.
Jørgensen, T.
Karaleftheri, M.
Khor, C.C.
Kirkpatrick, A.
Kraja, A.T.
Kuusisto, J.
Lange, E.M.
Lee, I.T.
Lee, W.-J.
Leong, A.
Liao, J.
Liu, C.
Liu, Y.
Lindgren, C.M.
Linneberg, A.
Malerba, G.
Mamakou, V.
Marouli, E.
Maruthur, N.M.
Matchan, A.
McKean-Cowdin, R.
McLeod, O.
Metcalf, G.A.
Mohlke, K.L.
Muzny, D.M.
Ntalla, I.
Palmer, N.D.
Pasko, D.
Peter, A.
Rayner, N.W.
Renström, F.
Rice, K.
Sala, C.F.
Sennblad, B.
Serafetinidis, I.
Smith, J.A.
Soranzo, N.
Speliotes, E.K.
Stahl, E.A.
Stirrups, K.
Tentolouris, N.
Thanopoulou, A.
Torres, M.
Traglia, M.
Tsafantakis, E.
Javad, S.
Yanek, L.R.
Zengini, E.
Becker, D.M.
Bis, J.C.
Brown, J.B.
Adrienne Cupples, L.
Hansen, T.
Ingelsson, E.
Karter, A.J.
Lorenzo, C.
Mathias, R.A.
Norris, J.M.
Peloso, G.M.
Sheu, W.H.-H.
Toniolo, D.
Vaidya, D.
Varma, R.
Wagenknecht, L.E.
Boeing, H.
Bottinger, E.P.
Dedoussis, G.
Deloukas, P.
Ferrannini, E.
Franco, O.H.
Franks, P.W.
Gibbs, R.A.
Gudnason, V.
Hamsten, A.
Harris, T.B.
Hattersley, A.T.
Hayward, C.
Hofman, A.
Jansson, J.-H.
Langenberg, C.
Launer, L.J.
Levy, D.
Oostra, B.A.
O'Donnell, C.J.
O'Rahilly, S.
Padmanabhan, S.
Pankow, J.S.
Polasek, O.
Province, M.A.
Rich, S.S.
Ridker, P.M.
Rudan, I.
Schulze, M.B.
Smith, B.H.
Uitterlinden, A.G.
Walker, M.
Watkins, H.
Wong, T.Y.
Zeggini, E.
Laakso, M.
Borecki, I.B.
Chasman, D.I.
Pedersen, O.
Psaty, B.M.
Shyong Tai, E.
Van Duijn, C.M.
Wareham, N.J.
Waterworth, D.M.
Boerwinkle, E.
Linda Kao, W.H.
Florez, J.C.
Loos, R.J.F.
Wilson, J.G.
Frayling, T.M.
Siscovick, D.S.
Dupuis, J.
Rotter, J.I.
Meigs, J.B.
Scott, R.A.
Goodarzi, M.O.
Περιοδικό:
Nature Communications
Εκδότης:
Nature Publishing Group
Τόμος:
6
Λέξεις-κλειδιά:
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
Επίσημο URL (Εκδότης):
DOI:
10.1038/ncomms6897
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