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

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

Nature communications (2015-01-30)

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

PMID25631608

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.

MATERIALS

Product Number

Brand

Product Description

47127-U

Supelco

Cholesterol solution, certified reference material, 10 mg/mL in chloroform

S5442

Sigma-Aldrich

SyntheChol^® NS0 Supplement, 500 ×, synthetic cholesterol, animal component-free, aqueous solution, sterile-filtered, suitable for cell culture

14606

Sigma-Aldrich