Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Authors: Wessel Jennifer , Chu Audrey Y , Willems Sara M , Wang Shuai , Yaghootkar Hanieh , Brody Jennifer A , Dauriz Marco , Hivert Marie-France , Raghavan Sridharan , Lipovich Leonard , Hidalgo Bertha , Fox Keolu , Huffman Jennifer E , An Ping , Lu Yingchang , Rasmussen-Torvik Laura J , Grarup Niels , Ehm Margaret G , Li Li , Baldridge Abigail S , Stančáková Alena , Abrol Ravinder , Besse Céline , Boland Anne , Bork-Jensen Jette , Fornage Myriam , Freitag Daniel F , Garcia Melissa E , Guo Xiuqing , Hara Kazuo , Isaacs Aaron , Jakobsdottir Johanna , Lange Leslie A , Layton Jill C , Li Man , Hua Zhao Jing , Meidtner Karina , Morrison Alanna C , Nalls Mike A , Peters Marjolein J , Sabater-Lleal Maria , Schurmann Claudia , Silveira Angela , Smith Albert V , Southam Lorraine , Stoiber Marcus H , Strawbridge Rona J , Taylor Kent D , Varga Tibor V , Allin Kristine H , Amin Najaf , Aponte Jennifer L , Aung Tin , Barbieri Caterina , Bihlmeyer Nathan A , Boehnke Michael , Bombieri Cristina , Bowden Donald W , Burns Sean M , Chen Yuning , Chen Yii-DerI , Cheng Ching-Yu , Correa Adolfo , Czajkowski Jacek , Dehghan Abbas , Ehret Georg B , Eiriksdottir Gudny , Escher Stefan A , Farmaki Aliki-Eleni , Frånberg Mattias , Gambaro Giovanni , Giulianini Franco , Goddard William A , Goel Anuj , Gottesman Omri , Grove Megan L , Gustafsson Stefan , Hai Yang , Hallmans Göran , Heo Jiyoung , Hoffmann Per , Ikram Mohammad K , Jensen Richard A , Jørgensen Marit E , Jørgensen Torben , Karaleftheri Maria , Khor Chiea C , Kirkpatrick Andrea , Kraja Aldi T , Kuusisto Johanna , Lange Ethan M , Lee I T , Lee Wen-Jane , Leong Aaron , Liao Jiemin , Liu Chunyu , Liu Yongmei , Lindgren Cecilia M , Linneberg Allan , Malerba Giovanni , Mamakou Vasiliki , Marouli Eirini , Maruthur Nisa M , Matchan Angela , McKean-Cowdin Roberta , McLeod Olga , Metcalf Ginger A , Mohlke Karen L , Muzny Donna M , Ntalla Ioanna , Palmer Nicholette D , Pasko Dorota , Peter Andreas , Rayner Nigel W , Renström Frida , Rice Ken , Sala Cinzia F , Sennblad Bengt , Serafetinidis Ioannis , Smith Jennifer A , Soranzo Nicole , Speliotes Elizabeth K , Stahl Eli A , Stirrups Kathleen , Tentolouris Nikos , Thanopoulou Anastasia , Torres Mina , Traglia Michela , Tsafantakis Emmanouil , Javad Sundas , Yanek Lisa R , Zengini Eleni , Becker Diane M , Bis Joshua C , Brown James B , Adrienne Cupples L , Hansen Torben , Ingelsson Erik , Karter Andrew J , Lorenzo Carlos , Mathias Rasika A , Norris Jill M , Peloso Gina M , Sheu Wayne H.-H. , Toniolo Daniela , Vaidya Dhananjay , Varma Rohit , Wagenknecht Lynne E , Boeing Heiner , Bottinger Erwin P , Dedoussis George , Deloukas Panos , Ferrannini Ele , Franco Oscar H , Franks Paul W , Gibbs Richard A , Gudnason Vilmundur , Hamsten Anders , Harris Tamara B , Hattersley Andrew T , Hayward Caroline , Hofman Albert , Jansson Jan-Håkan , Langenberg Claudia , Launer Lenore J , Levy Daniel , Oostra Ben A , O’Donnell Christopher J , O’Rahilly Stephen , Padmanabhan Sandosh , Pankow James S , Polasek Ozren , Province Michael A , Rich Stephen S , Ridker Paul M , Rudan Igor , Schulze Matthias B , Smith Blair H , Uitterlinden André G , Walker Mark , Watkins Hugh , Wong Tien Y , Zeggini Eleftheria ,   The EPIC-InterAct Consortium, Sharp Stephen J , Forouhi Nita G , Kerrison Nicola D , Lucarelli Debora ME , Sims Matt , Barroso Inês , McCarthy Mark I , Arriola Larraitz , Balkau Beverley , Barricarte Aurelio , Gonzalez Carlos , Grioni Sara , Kaaks Rudolf , Key Timothy J , Navarro Carmen , Nilsson Peter M , Overvad Kim , Palli Domenico , Panico Salvatore , Quirós J. Ramón , Rolandsson Olov , Sacerdote Carlotta , Sánchez María–José , Slimani Nadia , Tjonneland Anne , Tumino Rosario , van der A Daphne L , van der Schouw Yvonne T , Riboli Elio , Laakso Markku , Borecki Ingrid B , Chasman Daniel I , Pedersen Oluf , Psaty Bruce M , Shyong Tai E , van Duijn Cornelia M , Wareham Nicholas J , Waterworth Dawn M , Boerwinkle Eric , Linda Kao W H , Florez Jose C , Loos Ruth J.F. , Wilson James G , Frayling Timothy M , Siscovick David S , Dupuis Josée , Rotter Jerome I , Meigs James B , Scott Robert A , Goodarzi Mark O 
Published: January 2015

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.