Publication

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

Journal Paper/Review - Jan 29, 2015

Units
PubMed
Doi

Citation
Franco O, Lorenzo C, Karter A, Ingelsson E, Hansen T, Cupples L, Brown J, Bis J, Becker D, Zengini E, Yanek L, Mathias R, Norris J, Peloso G, Ferrannini E, Deloukas P, Dedoussis G, Bottinger E, Boeing H, Wagenknecht L, Varma R, Vaidya D, Toniolo D, Sheu W, Javad S, Tsafantakis E, Traglia M, Rayner N, Peter A, Pasko D, Palmer N, Ntalla I, Muzny D, Mohlke K, Metcalf G, McLeod O, McKean-Cowdin R, Renström F, Rice K, Sala C, Torres M, Thanopoulou A, Tentolouris N, Stirrups K, Stahl E, Speliotes E, Soranzo N, Smith J, Serafetinidis I, Sennblad B, Matchan A, Goodarzi M, van Duijn C, Tai E, Psaty B, Pedersen O, Chasman D, Borecki I, Laakso M, Zeggini E, Wong T, Wareham N, Waterworth D, Boerwinkle E, Scott R, Meigs J, Rotter J, Dupuis J, Siscovick D, Frayling T, Wilson J, Loos R, Florez J, Kao W, Watkins H, Walker M, Uitterlinden A, Launer L, Langenberg C, Jansson J, Hofman A, Hayward C, Hattersley A, Harris T, Hamsten A, Gudnason V, Gibbs R, Levy D, Oostra B, O'Donnell C, Smith B, Schulze M, Rudan I, Ridker P, Rich S, Province M, Polasek O, Pankow J, Padmanabhan S, O'Rahilly S, Franks P, Maruthur N, Amin N, Meidtner K, Hua Zhao J, Li M, Layton J, Lange L, Jakobsdottir J, Isaacs A, Hara K, Guo X, Garcia M, Morrison A, Nalls M, Peters M, Allin K, Varga T, Taylor K, Strawbridge R, Stoiber M, Southam L, Smith A, Silveira A, Schurmann C, Sabater-Lleal M, Freitag D, Fornage M, Bork-Jensen J, Hidalgo B, Lipovich L, Raghavan S, Hivert M, Dauriz M, Brody J, Yaghootkar H, Wang S, Willems S, Chu A, Fox K, Huffman J, An P, Boland A, Besse C, Abrol R, Stančáková A, Baldridge A, Li L, Ehm M, Grarup N, Rasmussen-Torvik L, Lu Y, Wessel J, Marouli E, Kirkpatrick A, Khor C, Karaleftheri M, Jørgensen T, Jørgensen M, Jensen R, Ikram M, Hoffmann P, Heo J, Hallmans G, Kraja A, Kuusisto J, Lange E, Mamakou V, Malerba G, Linneberg A, Lindgren C, Liu Y, Liu C, Liao J, Leong A, Lee W, Lee I, Hai Y, Gustafsson S, Grove M, Cheng C, Chen Y, Chen Y, Burns S, Bowden D, Bombieri C, Boehnke M, Bihlmeyer N, Barbieri C, Aung T, Correa A, Czajkowski J, Dehghan A, Gottesman O, Goel A, Goddard W, Giulianini F, Gambaro G, Frånberg M, Farmaki A, Escher S, Eiriksdottir G, Ehret G, Aponte J. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun 2015; 6:5897.
Type
Journal Paper/Review (English)
Journal
Nat Commun 2015; 6
Publication Date
Jan 29, 2015
Issn Electronic
2041-1723
Pages
5897
Brief description/objective

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.