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

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. BaldridgeAlena 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 W. 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

Research output: Contribution to journalArticle

90 Citations (Scopus)

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±0.01mmoll-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±0.035pmolinsulin mmolglucose -1, P=0.048), but higher 2-h glucose (β=0.16±0.05mmoll-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (p SKAT =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±0.004mmoll-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.

Original languageEnglish
Article number6897
JournalNature Communications
Volume6
DOIs
StatePublished - 2015

Fingerprint

fasting
Exome
Medical problems
glucose
Type 2 Diabetes Mellitus
Fasting
insulin
coding
chips
Long Noncoding RNA
Insulin
low frequencies
magnetic permeability
Glucose
Introns
secretions
Genes
genes
proteins
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

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

In: Nature Communications, Vol. 6, 6897, 2015.

Research output: Contribution to journalArticle

Wessel, J, Chu, AY, Willems, SM, Wang, S, Yaghootkar, H, Brody, JA, Dauriz, M, Hivert, MF, Raghavan, S, Lipovich, L, Hidalgo, B, Fox, K, Huffman, JE, An, P, Lu, Y, Rasmussen-Torvik, LJ, Grarup, N, Ehm, MG, Li, L, Baldridge, AS, Stančáková, A, Abrol, R, Besse, C, Boland, A, Bork-Jensen, J, Fornage, M, Freitag, DF, Garcia, ME, Guo, X, Hara, K, Isaacs, A, Jakobsdottir, J, Lange, LA, Layton, JC, Li, M, Hua Zhao, J, Meidtner, K, Morrison, AC, Nalls, MA, Peters, MJ, Sabater-Lleal, M, Schurmann, C, Silveira, A, Smith, AV, Southam, L, Stoiber, MH, Strawbridge, RJ, Taylor, KD, Varga, TV, Allin, KH, Amin, N, Aponte, JL, Aung, T, Barbieri, C, Bihlmeyer, NA, Boehnke, M, Bombieri, C, Bowden, DW, Burns, SM, Chen, Y, Chen, YD, Cheng, CY, Correa, A, Czajkowski, J, Dehghan, A, Ehret, GB, Eiriksdottir, G, Escher, SA, Farmaki, AE, Frånberg, M, Gambaro, G, Giulianini, F, Goddard, WA, Goel, A, Gottesman, O, Grove, ML, Gustafsson, S, Hai, Y, Hallmans, G, Heo, J, Hoffmann, P, Ikram, MK, Jensen, RA, Jørgensen, ME, Jørgensen, T, Karaleftheri, M, Khor, CC, Kirkpatrick, A, Kraja, AT, Kuusisto, J, Lange, EM, Lee, IT, Lee, WJ, Leong, A, Liao, J, Liu, C, Liu, Y, Lindgren, CM, Linneberg, A, Malerba, G, Mamakou, V, Marouli, E, Maruthur, NM, Matchan, A, McKean-Cowdin, R, McLeod, O, Metcalf, GA, Mohlke, KL, Muzny, DM, Ntalla, I, Palmer, ND, Pasko, D, Peter, A, Rayner, NW, Renström, F, Rice, K, Sala, CF, Sennblad, B, Serafetinidis, I, Smith, JA, Soranzo, N, Speliotes, EK, Stahl, EA, Stirrups, K, Tentolouris, N, Thanopoulou, A, Torres, M, Traglia, M, Tsafantakis, E, Javad, S, Yanek, LR, Zengini, E, Becker, DM, Bis, JC, Brown, JB, Adrienne Cupples, L, Hansen, T, Ingelsson, E, Karter, AJ, Lorenzo, C, Mathias, RA, Norris, JM, Peloso, GM, Sheu, WHH, Toniolo, D, Vaidya, D, Varma, R, Wagenknecht, LE, Boeing, H, Bottinger, EP, Dedoussis, G, Deloukas, P, Ferrannini, E, Franco, OH, Franks, PW, Gibbs, RA, Gudnason, V, Hamsten, A, Harris, TB, Hattersley, AT, Hayward, C, Hofman, A, Jansson, JH, Langenberg, C, Launer, LJ, Levy, D, Oostra, BA, O'Donnell, CJ, O'Rahilly, S, Padmanabhan, S, Pankow, JS, Polasek, O, Province, MA, Rich, SS, Ridker, PM, Rudan, I, Schulze, MB, Smith, BH, Uitterlinden, AG, Walker, M, Watkins, H, Wong, TY, Zeggini, E, Laakso, M, Borecki, IB, Chasman, DI, Pedersen, O, Psaty, BM, Shyong Tai, E, Van Duijn, CM, Wareham, NJ, Waterworth, DM, Boerwinkle, E, Linda Kao, WH, Florez, JC, Loos, RJF, Wilson, JG, Frayling, TM, Siscovick, DS, Dupuis, J, Rotter, JI, Meigs, JB, Scott, RA & Goodarzi, MO 2015, 'Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility', Nature Communications, vol. 6, 6897. https://doi.org/10.1038/ncomms6897
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 ; 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. / Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. In: Nature Communications. 2015 ; Vol. 6.
@article{bded70c92e544ffdafc275f4bcc91bac,
title = "Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility",
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±0.01mmoll-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±0.035pmolinsulin mmolglucose -1, P=0.048), but higher 2-h glucose (β=0.16±0.05mmoll-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (p SKAT =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±0.004mmoll-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.",
author = "Jennifer Wessel and Chu, {Audrey Y.} and Willems, {Sara M.} and Shuai Wang and Hanieh Yaghootkar and Brody, {Jennifer A.} and Marco Dauriz and Hivert, {Marie France} and Sridharan Raghavan and Leonard Lipovich and Bertha Hidalgo and Keolu Fox and Huffman, {Jennifer E.} and Ping An and Yingchang Lu and Rasmussen-Torvik, {Laura J.} and Niels Grarup and Ehm, {Margaret G.} and Li Li and Baldridge, {Abigail S.} and Alena Stanč{\'a}kov{\'a} and Ravinder Abrol and C{\'e}line Besse and Anne Boland and Jette Bork-Jensen and Myriam Fornage and Freitag, {Daniel F.} and Garcia, {Melissa E.} and Xiuqing Guo and Kazuo Hara and Aaron Isaacs and Johanna Jakobsdottir and Lange, {Leslie A.} and Layton, {Jill C.} and Man Li and {Hua Zhao}, Jing and Karina Meidtner and Morrison, {Alanna C.} and Nalls, {Mike A.} and Peters, {Marjolein J.} and Maria Sabater-Lleal and Claudia Schurmann and Angela Silveira and Smith, {Albert V.} and Lorraine Southam and Stoiber, {Marcus H.} and Strawbridge, {Rona J.} and Taylor, {Kent D.} and Varga, {Tibor V.} and Allin, {Kristine H.} and Najaf Amin and Aponte, {Jennifer L.} and Tin Aung and Caterina Barbieri and Bihlmeyer, {Nathan A.} and Michael Boehnke and Cristina Bombieri and Bowden, {Donald W.} and Burns, {Sean M.} and Yuning Chen and Chen, {Yii Deri} and Cheng, {Ching Yu} and Adolfo Correa and Jacek Czajkowski and Abbas Dehghan and Ehret, {Georg B.} and Gudny Eiriksdottir and Escher, {Stefan A.} and Farmaki, {Aliki Eleni} and Mattias Fr{\aa}nberg and Giovanni Gambaro and Franco Giulianini and Goddard, {William A.} and Anuj Goel and Omri Gottesman and Grove, {Megan L.} and Stefan Gustafsson and Yang Hai and G{\"o}ran Hallmans and Jiyoung Heo and Per Hoffmann and Ikram, {Mohammad K.} and Jensen, {Richard A.} and J{\o}rgensen, {Marit E.} and Torben J{\o}rgensen and Maria Karaleftheri and Khor, {Chiea C.} and Andrea Kirkpatrick and Kraja, {Aldi T.} and Johanna Kuusisto and Lange, {Ethan M.} and Lee, {I. T.} and Lee, {Wen Jane} and Aaron Leong and Jiemin Liao and Chunyu Liu and Yongmei Liu and Lindgren, {Cecilia M.} and Allan Linneberg and Giovanni Malerba and Vasiliki Mamakou and Eirini Marouli and Maruthur, {Nisa M.} and Angela Matchan and Roberta McKean-Cowdin and Olga McLeod and Metcalf, {Ginger A.} and Mohlke, {Karen L.} and Muzny, {Donna M.} and Ioanna Ntalla and Palmer, {Nicholette D.} and Dorota Pasko and Andreas Peter and Rayner, {Nigel W.} and Frida Renstr{\"o}m and Ken Rice and Sala, {Cinzia F.} and Bengt Sennblad and Ioannis Serafetinidis and Smith, {Jennifer A.} and Nicole Soranzo and Speliotes, {Elizabeth K.} and Stahl, {Eli A.} and Kathleen Stirrups and Nikos Tentolouris and Anastasia Thanopoulou and Mina Torres and Michela Traglia and Emmanouil Tsafantakis and Sundas Javad and Yanek, {Lisa R.} and Eleni Zengini and Becker, {Diane M.} and Bis, {Joshua C.} and Brown, {James B.} and {Adrienne Cupples}, L. and Torben Hansen and Erik Ingelsson and Karter, {Andrew J.} and Carlos Lorenzo and Mathias, {Rasika A.} and Norris, {Jill M.} and Peloso, {Gina M.} and Sheu, {Wayne H H} and Daniela Toniolo and Dhananjay Vaidya and Rohit Varma and Wagenknecht, {Lynne E.} and Heiner Boeing and Bottinger, {Erwin P.} and George Dedoussis and Panos Deloukas and Ele Ferrannini and Franco, {Oscar H.} and Franks, {Paul W.} and Gibbs, {Richard A.} and Vilmundur Gudnason and Anders Hamsten and Harris, {Tamara B.} and Hattersley, {Andrew T.} and Caroline Hayward and Albert Hofman and Jansson, {Jan H{\aa}kan} and Claudia Langenberg and Launer, {Lenore J.} and Daniel Levy and Oostra, {Ben A.} and O'Donnell, {Christopher J.} and Stephen O'Rahilly and Sandosh Padmanabhan and Pankow, {James S.} and Ozren Polasek and Province, {Michael A.} and Rich, {Stephen S.} and Ridker, {Paul M.} and Igor Rudan and Schulze, {Matthias B.} and Smith, {Blair H.} and Uitterlinden, {Andr{\'e} G.} and Mark Walker and Hugh Watkins and Wong, {Tien Y.} and Eleftheria Zeggini and Markku Laakso and Borecki, {Ingrid B.} and Chasman, {Daniel I.} and Oluf Pedersen and Psaty, {Bruce M.} and {Shyong Tai}, E. and {Van Duijn}, {Cornelia M.} and Wareham, {Nicholas J.} and Waterworth, {Dawn M.} and Eric Boerwinkle and {Linda Kao}, {W. H.} and Florez, {Jose C.} and Loos, {Ruth J F} and Wilson, {James G.} and Frayling, {Timothy M.} and Siscovick, {David S.} and Jos{\'e}e Dupuis and Rotter, {Jerome I.} and Meigs, {James B.} and Scott, {Robert A.} and Goodarzi, {Mark O.}",
year = "2015",
doi = "10.1038/ncomms6897",
language = "English",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

AU - Wessel, Jennifer

AU - Chu, Audrey Y.

AU - Willems, Sara M.

AU - Wang, Shuai

AU - Yaghootkar, Hanieh

AU - Brody, Jennifer A.

AU - Dauriz, Marco

AU - Hivert, Marie France

AU - Raghavan, Sridharan

AU - Lipovich, Leonard

AU - Hidalgo, Bertha

AU - Fox, Keolu

AU - Huffman, Jennifer E.

AU - An, Ping

AU - Lu, Yingchang

AU - Rasmussen-Torvik, Laura J.

AU - Grarup, Niels

AU - Ehm, Margaret G.

AU - Li, Li

AU - Baldridge, Abigail S.

AU - Stančáková, Alena

AU - Abrol, Ravinder

AU - Besse, Céline

AU - Boland, Anne

AU - Bork-Jensen, Jette

AU - Fornage, Myriam

AU - Freitag, Daniel F.

AU - Garcia, Melissa E.

AU - Guo, Xiuqing

AU - Hara, Kazuo

AU - Isaacs, Aaron

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PY - 2015

Y1 - 2015

N2 - 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±0.01mmoll-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±0.035pmolinsulin mmolglucose -1, P=0.048), but higher 2-h glucose (β=0.16±0.05mmoll-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (p SKAT =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±0.004mmoll-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.

AB - 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±0.01mmoll-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±0.035pmolinsulin mmolglucose -1, P=0.048), but higher 2-h glucose (β=0.16±0.05mmoll-1, P=4.3 × 10-4). We identify a gene-based association with FG at G6PC2 (p SKAT =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±0.004mmoll-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.

UR - http://www.scopus.com/inward/record.url?scp=84923206532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923206532&partnerID=8YFLogxK

U2 - 10.1038/ncomms6897

DO - 10.1038/ncomms6897

M3 - Article

C2 - 25631608

AN - SCOPUS:84923206532

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6897

ER -