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 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 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 () and Mark O Goodarzi ()
Additional contact information
Jennifer Wessel: Fairbanks School of Public Health
Audrey Y Chu: Brigham and Women’s Hospital
Sara M Willems: Genetic Epidemiology Unit, Erasmus University Medical Center
Shuai Wang: Boston University School of Public Health
Hanieh Yaghootkar: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter
Jennifer A Brody: Cardiovascular Health Research Unit, University of Washington
Marco Dauriz: Massachusetts General Hospital
Marie-France Hivert: Harvard Pilgrim Health Care Institute, Harvard Medical School
Sridharan Raghavan: Massachusetts General Hospital
Leonard Lipovich: Center for Molecular Medicine and Genetics, Wayne State University
Bertha Hidalgo: University of Alabama at Birmingham
Keolu Fox: University of Washington
Jennifer E Huffman: National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study
Ping An: Washington University School of Medicine
Yingchang Lu: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
Laura J Rasmussen-Torvik: Northwestern University Feinberg School of Medicine
Niels Grarup: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Margaret G Ehm: Quantitative Sciences, PCPS
Li Li: Quantitative Sciences, PCPS
Abigail S Baldridge: Northwestern University Feinberg School of Medicine
Alena Stančáková: Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland
Ravinder Abrol: Cedars-Sinai Medical Center
Céline Besse: CEA, Institut de Génomique, Centre National de Génotypage
Anne Boland: CEA, Institut de Génomique, Centre National de Génotypage
Jette Bork-Jensen: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Myriam Fornage: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center
Daniel F Freitag: The Wellcome Trust Sanger Institute
Melissa E Garcia: Intramural Research Program, National Institute on Aging
Xiuqing Guo: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Kazuo Hara: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
Aaron Isaacs: Genetic Epidemiology Unit, Erasmus University Medical Center
Johanna Jakobsdottir: Icelandic Heart Association
Leslie A Lange: University of North Carolina
Jill C Layton: Indiana University, Fairbanks School of Public Health
Man Li: Johns Hopkins University
Jing Hua Zhao: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Karina Meidtner: German Institute of Human Nutrition Potsdam-Rehbrücke
Alanna C Morrison: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
Mike A Nalls: Laboratory of Neurogenetics, National Institute on Aging
Marjolein J Peters: Erasmus University Medical Center
Maria Sabater-Lleal: Atherosclerosis Research Unit, Karolinska Institutet
Claudia Schurmann: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
Angela Silveira: Atherosclerosis Research Unit, Karolinska Institutet
Albert V Smith: Icelandic Heart Association
Lorraine Southam: The Wellcome Trust Sanger Institute
Marcus H Stoiber: Lawrence Berkeley National Laboratory
Rona J Strawbridge: Atherosclerosis Research Unit, Karolinska Institutet
Kent D Taylor: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Tibor V Varga: Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital
Kristine H Allin: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Najaf Amin: Genetic Epidemiology Unit, Erasmus University Medical Center
Jennifer L Aponte: Quantitative Sciences, PCPS
Tin Aung: Singapore Eye Research Institute, Singapore National Eye Centre
Caterina Barbieri: San Raffaele Research Institute
Nathan A Bihlmeyer: Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Michael Boehnke: University of Michigan
Cristina Bombieri: Section of Biology and Genetics, University of Verona
Donald W Bowden: Wake Forest School of Medicine
Sean M Burns: Diabetes Unit, Massachusetts General Hospital
Yuning Chen: Boston University School of Public Health
Yii-DerI Chen: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Ching-Yu Cheng: Singapore Eye Research Institute, Singapore National Eye Centre
Adolfo Correa: University of Mississippi Medical Center
Jacek Czajkowski: Washington University School of Medicine
Abbas Dehghan: Erasmus University Medical Center
Georg B Ehret: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University
Gudny Eiriksdottir: Icelandic Heart Association
Stefan A Escher: Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital
Aliki-Eleni Farmaki: School of Health Science and Education, Harokopio University
Mattias Frånberg: Atherosclerosis Research Unit, Karolinska Institutet
Giovanni Gambaro: Columbus-Gemelli University Hospital, Catholic University
Franco Giulianini: Brigham and Women’s Hospital
William A Goddard: Materials and Process Simulation Center, California Institute of Technology
Anuj Goel: The Wellcome Trust Centre for Human Genetics, University of Oxford
Omri Gottesman: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
Megan L Grove: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
Stefan Gustafsson: Molecular Epidemiology and Science for Life Laboratory, Uppsala University
Yang Hai: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Göran Hallmans: Umeå University
Jiyoung Heo: Sangmyung University
Per Hoffmann: Institute of Human Genetics, Life & Brain Center, University of Bonn
Mohammad K Ikram: Singapore Eye Research Institute, Singapore National Eye Centre
Richard A Jensen: Cardiovascular Health Research Unit, University of Washington
Marit E Jørgensen: Steno Diabetes Center
Torben Jørgensen: Research Centre for Prevention and Health, Glostrup University Hospital
Maria Karaleftheri: Echinos Medical Centre
Chiea C Khor: National University of Singapore and National University Health System
Andrea Kirkpatrick: Materials and Process Simulation Center, California Institute of Technology
Aldi T Kraja: Washington University School of Medicine
Johanna Kuusisto: Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital
Ethan M Lange: University of North Carolina
I T Lee: Taichung Veterans General Hospital
Wen-Jane Lee: Taichung Veterans General Hospital
Aaron Leong: Massachusetts General Hospital
Jiemin Liao: Singapore Eye Research Institute, Singapore National Eye Centre
Chunyu Liu: National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study
Yongmei Liu: Wake Forest University
Cecilia M Lindgren: Wellcome Trust Centre for Human Genetics, University of Oxford
Allan Linneberg: Research Centre for Prevention and Health, Glostrup University Hospital
Giovanni Malerba: Section of Biology and Genetics, University of Verona
Vasiliki Mamakou: National and Kapodistrian University of Athens, Faculty of Medicine
Eirini Marouli: School of Health Science and Education, Harokopio University
Nisa M Maruthur: Johns Hopkins University School of Medicine
Angela Matchan: The Wellcome Trust Sanger Institute
Roberta McKean-Cowdin: Keck School of Medicine of the University of Southern California
Olga McLeod: Atherosclerosis Research Unit, Karolinska Institutet
Ginger A Metcalf: Human Genome Sequencing Center, Baylor College of Medicine
Karen L Mohlke: University of North Carolina
Donna M Muzny: Human Genome Sequencing Center, Baylor College of Medicine
Ioanna Ntalla: School of Health Science and Education, Harokopio University
Nicholette D Palmer: Wake Forest School of Medicine
Dorota Pasko: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter
Andreas Peter: Metabolism, Pathobiochemistry and Clinical Chemistry and Institute of Diabetes Research and Metabolic Diseases, University of Tübingen
Nigel W Rayner: The Wellcome Trust Sanger Institute
Frida Renström: Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital
Ken Rice: Cardiovascular Health Research Unit, University of Washington
Cinzia F Sala: San Raffaele Research Institute
Bengt Sennblad: Atherosclerosis Research Unit, Karolinska Institutet
Ioannis Serafetinidis: Gennimatas General Hospital
Jennifer A Smith: School of Public Health, University of Michigan
Nicole Soranzo: The Wellcome Trust Sanger Institute
Elizabeth K Speliotes: University of Michigan
Eli A Stahl: The Icahn School of Medicine at Mount Sinai
Kathleen Stirrups: The Wellcome Trust Sanger Institute
Nikos Tentolouris: Athens University Medical School, Laiko General Hospital
Anastasia Thanopoulou: Diabetes Centre, National University of Athens, Hippokration General Hospital
Mina Torres: Keck School of Medicine of the University of Southern California
Michela Traglia: San Raffaele Research Institute
Emmanouil Tsafantakis: Anogia Medical Centre
Sundas Javad: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Lisa R Yanek: The GeneSTAR Research Program, The Johns Hopkins University School of Medicine
Eleni Zengini: Dromokaiteio Psychiatric Hospital
Diane M Becker: The GeneSTAR Research Program, The Johns Hopkins University School of Medicine
Joshua C Bis: Cardiovascular Health Research Unit, University of Washington
James B Brown: Lawrence Berkeley National Laboratory
L Adrienne Cupples: National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study
Torben Hansen: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Erik Ingelsson: Molecular Epidemiology and Science for Life Laboratory, Uppsala University
Andrew J Karter: Kaiser Permanente, Northern California Region
Carlos Lorenzo: University of Texas Health Science Center
Rasika A Mathias: The GeneSTAR Research Program, The Johns Hopkins University School of Medicine
Jill M Norris: Colorado School of Public Health, University of Colorado Denver
Gina M Peloso: Program in Medical and Population Genetics, Broad Institute
Wayne H.-H. Sheu: Taichung Veterans General Hospital
Daniela Toniolo: San Raffaele Research Institute
Dhananjay Vaidya: The GeneSTAR Research Program, The Johns Hopkins University School of Medicine
Rohit Varma: Keck School of Medicine of the University of Southern California
Lynne E Wagenknecht: Wake Forest School of Medicine
Heiner Boeing: German Institute of Human Nutrition Potsdam Rehbrücke
Erwin P Bottinger: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
George Dedoussis: School of Health Science and Education, Harokopio University
Panos Deloukas: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Ele Ferrannini: CNR Institute of Clinical Physiology
Oscar H Franco: Erasmus University Medical Center
Paul W Franks: Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital
Richard A Gibbs: Human Genome Sequencing Center, Baylor College of Medicine
Vilmundur Gudnason: Icelandic Heart Association
Anders Hamsten: Atherosclerosis Research Unit, Karolinska Institutet
Tamara B Harris: Intramural Research Program, National Institute on Aging
Andrew T Hattersley: Genetics of Diabetes, University of Exeter Medical School, University of Exeter
Caroline Hayward: MRC Human Genetics Unit, MRC IGMM, University of Edinburgh
Albert Hofman: Erasmus University Medical Center
Jan-Håkan Jansson: Umeå University
Claudia Langenberg: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Lenore J Launer: Intramural Research Program, National Institute on Aging
Daniel Levy: Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health
Ben A Oostra: Genetic Epidemiology Unit, Erasmus University Medical Center
Christopher J O’Donnell: National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study
Stephen O’Rahilly: University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Sandosh Padmanabhan: Institute of Cardiovascular and Medical Sciences, University of Glasgow
James S Pankow: School of Public Health, University of Minnesota
Ozren Polasek: Faculty of Medicine, University of Split
Michael A Province: Washington University School of Medicine
Stephen S Rich: Center for Public Health Genomics, University of Virginia
Paul M Ridker: Brigham and Women’s Hospital
Igor Rudan: Centre for Population Health Sciences, Medical School, University of Edinburgh
Matthias B Schulze: German Institute of Human Nutrition Potsdam-Rehbrücke
Blair H Smith: Medical Research Institute, University of Dundee
André G Uitterlinden: Erasmus University Medical Center
Mark Walker: Institute of Cellular Medicine, Newcastle University
Hugh Watkins: The Wellcome Trust Centre for Human Genetics, University of Oxford
Tien Y Wong: Singapore Eye Research Institute, Singapore National Eye Centre
Eleftheria Zeggini: The Wellcome Trust Sanger Institute
Markku Laakso: Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital
Ingrid B Borecki: Washington University School of Medicine
Daniel I Chasman: Brigham and Women’s Hospital
Oluf Pedersen: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Bruce M Psaty: Cardiovascular Health Research Unit, University of Washington
E Shyong Tai: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
Cornelia M van Duijn: Genetic Epidemiology Unit, Erasmus University Medical Center
Nicholas J Wareham: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Dawn M Waterworth: Genetics, PCPS, GlaxoSmithKline
Eric Boerwinkle: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
W H Linda Kao: Johns Hopkins University
Jose C Florez: Harvard Medical School
Ruth J.F. Loos: The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai
James G Wilson: University of Mississippi Medical Center
Timothy M Frayling: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter
David S Siscovick: New York Academy of Medicine
Josée Dupuis: National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study
Jerome I Rotter: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
James B Meigs: Massachusetts General Hospital
Robert A Scott: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Mark O Goodarzi: Cedars-Sinai Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms6897

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