- Main
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.
Published Web Location
https://doi.org/10.1038/ncomms6897Abstract
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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