- 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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