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

Author:
  • 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 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
Publishing year: 2015
Language: English
Publication/Series: Nature Communications
Volume: 6
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

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.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Genetic and Molecular Epidemiology
  • ISSN: 2041-1723
Paul Franks
E-mail: paul.franks [at] med.lu.se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49

60-12-021

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00