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

Publication

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

Journal Paper/Review - Jan 29, 2015

Franco Oscar H, Lorenzo Carlos, Karter Andrew J, Ingelsson Erik, Hansen Torben, Cupples L Adrienne, Brown James B, Bis Joshua C, Becker Diane M, Zengini Eleni, Yanek Lisa R, Mathias Rasika A, Norris Jill M, Peloso Gina M, Ferrannini Ele, Deloukas Panos, Dedoussis George, Bottinger Erwin P, Boeing Heiner, Wagenknecht Lynne E, Varma Rohit, Vaidya Dhananjay, Toniolo Daniela, Sheu Wayne H-H, Javad Sundas, Tsafantakis Emmanouil, Traglia Michela, Rayner Nigel W, Peter Andreas, Pasko Dorota, Palmer Nicholette D, Ntalla Ioanna, Muzny Donna M, Mohlke Karen L, Metcalf Ginger A, McLeod Olga, McKean-Cowdin Roberta, Renström Frida, Rice Ken, Sala Cinzia F, Torres Mina, Thanopoulou Anastasia, Tentolouris Nikos, Stirrups Kathleen, Stahl Eli A, Speliotes Elizabeth K, Soranzo Nicole, Smith Jennifer A, Serafetinidis Ioannis, Sennblad Bengt, Matchan Angela, Goodarzi Mark O, van Duijn Cornelia M, Tai E Shyong, Psaty Bruce M, Pedersen Oluf, Chasman Daniel I, Borecki Ingrid B, Laakso Markku, Zeggini Eleftheria, Wong Tien Y, Wareham Nicholas J, Waterworth Dawn M, Boerwinkle Eric, Scott Robert A, Meigs James B, Rotter Jerome I, Dupuis Josée, Siscovick David S, Frayling Timothy M, Wilson James G, Loos Ruth J F, Florez Jose C, Kao W H Linda, Watkins Hugh, Walker Mark, Uitterlinden André G, Launer Lenore J, Langenberg Claudia, Jansson Jan-Håkan, Hofman Albert, Hayward Caroline, Hattersley Andrew T, Harris Tamara B, Hamsten Anders, Gudnason Vilmundur, Gibbs Richard A, Levy Daniel, Oostra Ben A, O'Donnell Christopher J, Smith Blair H, Schulze Matthias B, Rudan Igor, Ridker Paul M, Rich Stephen S, Province Michael A, Polasek Ozren, Pankow James S, Padmanabhan Sandosh, O'Rahilly Stephen, Franks Paul W, Maruthur Nisa M, Amin Najaf, Meidtner Karina, Hua Zhao Jing, Li Man, Layton Jill C, Lange Leslie A, Jakobsdottir Johanna, Isaacs Aaron, Hara Kazuo, Guo Xiuqing, Garcia Melissa E, Morrison Alanna C, Nalls Mike A, Peters Marjolein J, Allin Kristine H, Varga Tibor V, Taylor Kent D, Strawbridge Rona J, Stoiber Marcus H, Southam Lorraine, Smith Albert V, Silveira Angela, Schurmann Claudia, Sabater-Lleal Maria, Freitag Daniel F, Fornage Myriam, Bork-Jensen Jette, Hidalgo Bertha, Lipovich Leonard, Raghavan Sridharan, Hivert Marie-France, Dauriz Marco, Brody Jennifer A, Yaghootkar Hanieh, Wang Shuai, Willems Sara M, Chu Audrey Y, Fox Keolu, Huffman Jennifer E, An Ping, Boland Anne, Besse Céline, Abrol Ravinder, Stančáková Alena, Baldridge Abigail S, Li Li, Ehm Margaret G, Grarup Niels, Rasmussen-Torvik Laura J, Lu Yingchang, Wessel Jennifer, Marouli Eirini, Kirkpatrick Andrea, Khor Chiea C, Karaleftheri Maria, Jørgensen Torben, Jørgensen Marit E, Jensen Richard A, Ikram Mohammad K, Hoffmann Per, Heo Jiyoung, Hallmans Göran, Kraja Aldi T, Kuusisto Johanna, Lange Ethan M, Mamakou Vasiliki, Malerba Giovanni, Linneberg Allan, Lindgren Cecilia M, Liu Yongmei, Liu Chunyu, Liao Jiemin, Leong Aaron, Lee Wen-Jane, Lee I T, Hai Yang, Gustafsson Stefan, Grove Megan L, Cheng Ching-Yu, Chen Yii-DerI, Chen Yuning, Burns Sean M, Bowden Donald W, Bombieri Cristina, Boehnke Michael, Bihlmeyer Nathan A, Barbieri Caterina, Aung Tin, Correa Adolfo, Czajkowski Jacek, Dehghan Abbas, Gottesman Omri, Goel Anuj, Goddard William A, Giulianini Franco, Gambaro Giovanni, Frånberg Mattias, Farmaki Aliki-Eleni, Escher Stefan A, Eiriksdottir Gudny, Ehret Georg B, Aponte Jennifer L

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.