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

  • Author(s): 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, IT
  • 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
  • Cupples, L Adrienne
  • 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
  • EPIC-InterAct Consortium
  • Laakso, Markku
  • Borecki, Ingrid B
  • Chasman, Daniel I
  • Pedersen, Oluf
  • Psaty, Bruce M
  • Tai, E Shyong
  • van Duijn, Cornelia M
  • Wareham, Nicholas J
  • Waterworth, Dawn M
  • Boerwinkle, Eric
  • Kao, WH Linda
  • Florez, Jose C
  • Loos, Ruth JF
  • Wilson, James G
  • Frayling, Timothy M
  • Siscovick, David S
  • Dupuis, Josée
  • Rotter, Jerome I
  • Meigs, James B
  • Scott, Robert A
  • Goodarzi, Mark O
  • et al.
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.

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