. 2015 Jan 29:6:5897.

doi: 10.1038/ncomms6897.

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

Jennifer Wessel¹, Audrey Y Chu², Sara M Willems³, Shuai Wang⁴, Hanieh Yaghootkar⁵, Jennifer A Brody⁶, Marco Dauriz⁷, Marie-France Hivert⁸, Sridharan Raghavan⁹, Leonard Lipovich¹⁰, Bertha Hidalgo¹¹, Keolu Fox¹², Jennifer E Huffman¹³, Ping An¹⁴, Yingchang Lu¹⁵, Laura J Rasmussen-Torvik¹⁶, Niels Grarup¹⁷, Margaret G Ehm¹⁸, Li Li¹⁸, Abigail S Baldridge¹⁶, Alena Stančáková¹⁹, Ravinder Abrol²⁰, Céline Besse²¹, Anne Boland²¹, Jette Bork-Jensen¹⁷, Myriam Fornage²², Daniel F Freitag²³, Melissa E Garcia²⁴, Xiuqing Guo²⁵, Kazuo Hara¹⁵, Aaron Isaacs²⁶, Johanna Jakobsdottir²⁷, Leslie A Lange²⁸, Jill C Layton²⁹, Man Li³⁰, Jing Hua Zhao³¹, Karina Meidtner³², Alanna C Morrison³³, Mike A Nalls³⁴, Marjolein J Peters³⁵, Maria Sabater-Lleal³⁶, Claudia Schurmann¹⁵, Angela Silveira³⁶, Albert V Smith³⁷, Lorraine Southam³⁸, Marcus H Stoiber³⁹, Rona J Strawbridge³⁶, Kent D Taylor²⁵, Tibor V Varga⁴⁰, Kristine H Allin¹⁷, Najaf Amin²⁶, Jennifer L Aponte¹⁸, Tin Aung⁴¹, Caterina Barbieri⁴², Nathan A Bihlmeyer⁴³, Michael Boehnke⁴⁴, Cristina Bombieri⁴⁵, Donald W Bowden⁴⁶, Sean M Burns⁴⁷, Yuning Chen⁴, Yii-DerI Chen²⁵, Ching-Yu Cheng⁴⁸, Adolfo Correa⁴⁹, Jacek Czajkowski¹⁴, Abbas Dehghan⁵⁰, Georg B Ehret⁵¹, Gudny Eiriksdottir²⁷, Stefan A Escher⁴⁰, Aliki-Eleni Farmaki⁵², Mattias Frånberg⁵³, Giovanni Gambaro⁵⁴, Franco Giulianini⁵⁵, William A Goddard 3rd⁵⁶, Anuj Goel⁵⁷, Omri Gottesman⁵⁸, Megan L Grove³³, Stefan Gustafsson⁵⁹, Yang Hai²⁵, Göran Hallmans⁶⁰, Jiyoung Heo⁶¹, Per Hoffmann⁶², Mohammad K Ikram⁶³, Richard A Jensen⁶, Marit E Jørgensen⁶⁴, Torben Jørgensen⁶⁵, Maria Karaleftheri⁶⁶, Chiea C Khor⁶⁷, Andrea Kirkpatrick⁵⁶, Aldi T Kraja¹⁴, Johanna Kuusisto⁶⁸, Ethan M Lange⁶⁹, I T Lee⁷⁰, Wen-Jane Lee⁷¹, Aaron Leong⁹, Jiemin Liao⁴¹, Chunyu Liu⁷², Yongmei Liu⁷³, Cecilia M Lindgren⁷⁴, Allan Linneberg⁷⁵, Giovanni Malerba⁴⁵, Vasiliki Mamakou⁷⁶, Eirini Marouli⁵², Nisa M Maruthur⁷⁷, Angela Matchan⁷⁸, Roberta McKean-Cowdin⁷⁹, Olga McLeod³⁶, Ginger A Metcalf⁸⁰, Karen L Mohlke²⁸, Donna M Muzny⁸⁰, Ioanna Ntalla⁸¹, Nicholette D Palmer⁸², Dorota Pasko⁵, Andreas Peter⁸³, Nigel W Rayner⁸⁴, Frida Renström⁴⁰, Ken Rice⁸⁵, Cinzia F Sala⁴², Bengt Sennblad⁸⁶, Ioannis Serafetinidis⁸⁷, Jennifer A Smith⁸⁸, Nicole Soranzo⁸⁹, Elizabeth K Speliotes⁹⁰, Eli A Stahl⁹¹, Kathleen Stirrups⁹², Nikos Tentolouris⁹³, Anastasia Thanopoulou⁹⁴, Mina Torres⁷⁹, Michela Traglia⁴², Emmanouil Tsafantakis⁹⁵, Sundas Javad³¹, Lisa R Yanek⁹⁶, Eleni Zengini⁹⁷, Diane M Becker⁹⁶, Joshua C Bis⁶, James B Brown⁹⁸, L Adrienne Cupples⁹⁹, Torben Hansen¹⁰⁰, Erik Ingelsson¹⁰¹, Andrew J Karter¹⁰², Carlos Lorenzo¹⁰³, Rasika A Mathias⁹⁶, Jill M Norris¹⁰⁴, Gina M Peloso¹⁰⁵, Wayne H-H Sheu¹⁰⁶, Daniela Toniolo⁴², Dhananjay Vaidya⁹⁶, Rohit Varma⁷⁹, Lynne E Wagenknecht¹⁰⁷, Heiner Boeing¹⁰⁸, Erwin P Bottinger⁵⁸, George Dedoussis⁵², Panos Deloukas¹⁰⁹, Ele Ferrannini¹¹⁰, Oscar H Franco⁵⁰, Paul W Franks¹¹¹, Richard A Gibbs⁸⁰, Vilmundur Gudnason³⁷, Anders Hamsten³⁶, Tamara B Harris²⁴, Andrew T Hattersley¹¹², Caroline Hayward¹¹³, Albert Hofman⁵⁰, Jan-Håkan Jansson¹¹⁴, Claudia Langenberg³¹, Lenore J Launer²⁴, Daniel Levy¹¹⁵, Ben A Oostra²⁶, Christopher J O'Donnell¹¹⁶, Stephen O'Rahilly¹¹⁷, Sandosh Padmanabhan¹¹⁸, James S Pankow¹¹⁹, Ozren Polasek¹²⁰, Michael A Province¹⁴, Stephen S Rich¹²¹, Paul M Ridker¹²², Igor Rudan¹²³, Matthias B Schulze¹²⁴, Blair H Smith¹²⁵, André G Uitterlinden¹²⁶, Mark Walker¹²⁷, Hugh Watkins⁵⁷, Tien Y Wong¹²⁸, Eleftheria Zeggini⁷⁸; EPIC-InterAct Consortium; Markku Laakso⁶⁸, Ingrid B Borecki¹⁴, Daniel I Chasman¹²⁹, Oluf Pedersen¹⁷, Bruce M Psaty¹³⁰, E Shyong Tai¹³¹, Cornelia M van Duijn¹³², Nicholas J Wareham³¹, Dawn M Waterworth¹³³, Eric Boerwinkle¹³⁴, W H Linda Kao¹³⁵, Jose C Florez¹³⁶, Ruth J F Loos¹³⁷, James G Wilson¹³⁸, Timothy M Frayling⁵, David S Siscovick¹³⁹, Josée Dupuis⁹⁹, Jerome I Rotter²⁵, James B Meigs⁹, Robert A Scott³¹, Mark O Goodarzi¹⁴⁰

Collaborators, Affiliations

Affiliations

¹ 1] Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA [2] Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
² 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA.
³ 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0SL, UK.
⁴ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
⁵ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
⁶ 1] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
⁷ 1] Massachusetts General Hospital, General Medicine Division, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona Medical School and Hospital Trust of Verona, Verona 37126, Italy.
⁸ 1] Harvard Pilgrim Health Care Institute, Department of Population Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Division of Endocrinology and Metabolism, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada J1K 2R1 [3] Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁹ 1] Massachusetts General Hospital, General Medicine Division, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
¹⁰ 1] Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA [2] Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48202, USA.
¹¹ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
¹² 1] Department of Medicine, University of Washington, Seattle, Washington 98195, USA [2] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
¹³ 1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA [2] MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland EH4 2XU, UK.
¹⁴ Division of Statistical Genomics and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
¹⁵ 1] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹⁶ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
¹⁷ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
¹⁸ Quantitative Sciences, PCPS, GlaxoSmithKline, North Carolina 27709, USA.
¹⁹ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio FI-70211, Finland.
²⁰ 1] Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA [2] Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, USA.
²¹ CEA, Institut de Génomique, Centre National de Génotypage, 2 Rue Gaston Crémieux, EVRY Cedex 91057, France.
²² Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA.
²³ 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
²⁴ Intramural Research Program, National Institute on Aging, Bethesda, Maryland 21224, USA.
²⁵ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
²⁶ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands.
²⁷ Icelandic Heart Association, Holtasmari 1, Kopavogur IS-201, Iceland.
²⁸ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
²⁹ Indiana University, Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA.
³⁰ Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
³¹ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0SL, UK.
³² Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal DE-14558, Germany.
³³ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas 77225, USA.
³⁴ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, USA.
³⁵ 1] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam 2300 RC, The Netherlands.
³⁶ Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm SE-171 77, Sweden.
³⁷ 1] Icelandic Heart Association, Holtasmari 1, Kopavogur IS-201, Iceland [2] University of Iceland, Reykjavik IS-101, Iceland.
³⁸ 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
³⁹ Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
⁴⁰ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital, Malmö SE-205 02, Sweden.
⁴¹ 1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [2] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore.
⁴² Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano 20132, Italy.
⁴³ 1] Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Maryland 21205, USA [2] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
⁴⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁴⁵ Section of Biology and Genetics, Department of Life and Reproduction Sciences, University of Verona, Verona 37100, Italy.
⁴⁶ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
⁴⁷ Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁴⁸ 1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [2] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore [3] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 119228, Singapore [4] Office of Clinical Sciences, Duke-NUS Graduate Medical School, National University of Singapore, Singapore 169857, Singapore.
⁴⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
⁵⁰ Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands.
⁵¹ 1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA [2] Division of Cardiology, Geneva University Hospital Geneva 1211, Switzerland.
⁵² Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece.
⁵³ 1] Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm SE-171 77, Sweden [2] Department of Numerical Analysis and Computer Science, SciLifeLab, Stockholm University, Stockholm SE-106 91, Sweden.
⁵⁴ Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Catholic University, Rome 00168, Italy.
⁵⁵ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
⁵⁶ Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, USA.
⁵⁷ Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁵⁸ The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
⁵⁹ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala SE-751 85, Sweden.
⁶⁰ Department of Biobank Research, Umeå University, Umeå SE-901 87, Sweden.
⁶¹ Department of Biomedical Technology, Sangmyung University, Chungnam 330-720, Korea.
⁶² 1] Institute of Human Genetics, Department of Genomics, Life &Brain Center, University of Bonn, Bonn DE-53127, Germany [2] Human Genomics Research Group, Division of Medical Genetics, University Hospital Basel Department of Biomedicine 4031, Basel, Switzerland [3] Institute of Neuroscience and Medicine (INM-1) Genomic Imaging Research Center Juelich, Juelich DE-52425, Germany.
⁶³ 1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [2] Office of Clinical Sciences, Duke-NUS Graduate Medical School, National University of Singapore, Singapore 169857, Singapore [3] Memory Aging &Cognition Centre (MACC), National University Health System, Singapore 117599, Singapore.
⁶⁴ Steno Diabetes Center, Gentofte DK-2820, Denmark.
⁶⁵ 1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup DK-2600, Denmark [2] Faculty of Medicine, University of Aalborg, Aalborg DK-9220, Denmark.
⁶⁶ Echinos Medical Centre, Echinos 67300, Greece.
⁶⁷ 1] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore [2] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 119228, Singapore [3] Division of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
⁶⁸ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio FI-70211, Finland.
⁶⁹ 1] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁷⁰ 1] Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan [2] School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
⁷¹ Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
⁷² National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA.
⁷³ Department of Epidemiology &Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina 27106, USA.
⁷⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁷⁵ 1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup DK-2600, Denmark [2] Department of Clinical Experimental Research, Copenhagen University Hospital Glostrup, Glostrup DK-2600, Denmark [3] Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
⁷⁶ 1] National and Kapodistrian University of Athens, Faculty of Medicine, Athens 115 27, Greece [2] Dromokaiteio Psychiatric Hospital, Athens 124 61, Greece.
⁷⁷ 1] Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland 21205, USA.
⁷⁸ The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
⁷⁹ Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles 90033, USA.
⁸⁰ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
⁸¹ 1] Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece [2] University of Leicester, Leicester LE1 7RH, UK.
⁸² 1] Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA [2] Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27106, USA.
⁸³ 1] Department of Internal Medicine, Division of Endocrinology, Metabolism, Pathobiochemistry and Clinical Chemistry and Institute of Diabetes Research and Metabolic Diseases, University of Tübingen, Tübingen DE-72076, Germany [2] German Center for Diabetes Research (DZD), Neuherberg DE-85764, Germany.
⁸⁴ 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK [3] The Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
⁸⁵ 1] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA [2] Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA.
⁸⁶ 1] Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm SE-171 77, Sweden [2] Science for Life Laboratory, Karolinska Institutet, Stockholm SE-171 77, Sweden.
⁸⁷ Department of Gastroenterology, Gennimatas General Hospital, Athens 11527, Greece.
⁸⁸ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁸⁹ 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Hematology, Long Road, Cambridge CB2 0XY, UK.
⁹⁰ Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁹¹ Division of Psychiatric Genomics, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
⁹² 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK.
⁹³ First Department of Propaedeutic and Internal Medicine, Athens University Medical School, Laiko General Hospital, Athens 11527, Greece.
⁹⁴ Diabetes Centre, 2nd Department of Internal Medicine, National University of Athens, Hippokration General Hospital, Athens 11527, Greece.
⁹⁵ Anogia Medical Centre, Anogia 740 51, Greece.
⁹⁶ The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
⁹⁷ 1] Dromokaiteio Psychiatric Hospital, Athens 124 61, Greece [2] University of Sheffield, Sheffield S10 2TN, UK.
⁹⁸ 1] Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [2] Department of Statistics, University of California at Berkeley, Berkeley, California 94720, USA.
⁹⁹ 1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
¹⁰⁰ 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark [2] Faculty of Health Science, University of Copenhagen, Copenhagen 1165, Denmark.
¹⁰¹ 1] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala SE-751 85, Sweden [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
¹⁰² Division of Research, Kaiser Permanente, Northern California Region, Oakland, California 94612, USA.
¹⁰³ Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 77030, USA.
¹⁰⁴ Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado 80204, USA.
¹⁰⁵ 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹⁰⁶ 1] Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan [2] School of Medicine, National Yang-Ming University, Taipei 112, Taiwan [3] College of Medicine, National Defense Medical Center, Taipei 114, Taiwan.
¹⁰⁷ Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27106, USA.
¹⁰⁸ Department of Epidemiology, German Institute of Human Nutrition Potsdam Rehbrücke, Nuthetal DE-14558, Germany.
¹⁰⁹ 1] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK [2] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK [3] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 22254, Saudi Arabia.
¹¹⁰ CNR Institute of Clinical Physiology, Pisa 73100, Italy.
¹¹¹ 1] Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital, Malmö SE-205 02, Sweden [2] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA [3] Department of Public Health &Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden.
¹¹² Genetics of Diabetes, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
¹¹³ MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland EH4 2XU, UK.
¹¹⁴ 1] Department of Public Health &Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden [2] Research Unit, Skellefteå SE-931 87, Sweden.
¹¹⁵ 1] Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Framingham Heart Study, Framingham, Massachusetts 01702, USA.
¹¹⁶ 1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
¹¹⁷ 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, Cambridge CB2 1TN, UK.
¹¹⁸ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
¹¹⁹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, USA.
¹²⁰ Department of Public Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
¹²¹ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22908, USA.
¹²² 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] Division of Cardiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
¹²³ Centre for Population Health Sciences, Medical School, University of Edinburgh, Edinburgh, Scotland EH8 9YL, UK.
¹²⁴ 1] Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal DE-14558, Germany [2] German Center for Diabetes Research (DZD), Neuherberg DE-85764, Germany.
¹²⁵ Medical Research Institute, University of Dundee, Dundee DD1 9SY, UK.
¹²⁶ 1] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands.
¹²⁷ Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK.
¹²⁸ 1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [2] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore [3] Office of Clinical Sciences, Duke-NUS Graduate Medical School, National University of Singapore, Singapore 169857, Singapore.
¹²⁹ 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹³⁰ 1] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA [3] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA [4] Department of Health Services, University of Washington, Seattle, Washington 98195, USA [5] Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98195, USA.
¹³¹ 1] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 119228, Singapore [2] Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
¹³² 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] Center for Medical Systems Biology, Leiden 2300, The Netherlands.
¹³³ Genetics, PCPS, GlaxoSmithKline, Philadelphia, Pennsylvania 19104, USA.
¹³⁴ 1] Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas 77225, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
¹³⁵ 1] Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21205, USA [2] Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland 21205, USA [3] Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
¹³⁶ 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA [4] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹³⁷ 1] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹³⁸ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 38677, USA.
¹³⁹ 1] New York Academy of Medicine, New York, New York 10029, USA [2] Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington 98195, USA.
¹⁴⁰ 1] Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA [2] Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

PMID: 25631608
PMCID: PMC4311266
DOI: 10.1038/ncomms6897

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

Jennifer Wessel et al. Nat Commun. 2015.

. 2015 Jan 29:6:5897.

doi: 10.1038/ncomms6897.

Authors

Affiliations

¹ 1] Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA [2] Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
² 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA.
³ 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0SL, UK.
⁴ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
⁵ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
⁶ 1] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
⁷ 1] Massachusetts General Hospital, General Medicine Division, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona Medical School and Hospital Trust of Verona, Verona 37126, Italy.
⁸ 1] Harvard Pilgrim Health Care Institute, Department of Population Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Division of Endocrinology and Metabolism, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada J1K 2R1 [3] Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁹ 1] Massachusetts General Hospital, General Medicine Division, Boston, Massachusetts 02114, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
¹⁰ 1] Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA [2] Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48202, USA.
¹¹ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
¹² 1] Department of Medicine, University of Washington, Seattle, Washington 98195, USA [2] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
¹³ 1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA [2] MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland EH4 2XU, UK.
¹⁴ Division of Statistical Genomics and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
¹⁵ 1] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹⁶ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
¹⁷ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
¹⁸ Quantitative Sciences, PCPS, GlaxoSmithKline, North Carolina 27709, USA.
¹⁹ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio FI-70211, Finland.
²⁰ 1] Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA [2] Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, USA.
²¹ CEA, Institut de Génomique, Centre National de Génotypage, 2 Rue Gaston Crémieux, EVRY Cedex 91057, France.
²² Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA.
²³ 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
²⁴ Intramural Research Program, National Institute on Aging, Bethesda, Maryland 21224, USA.
²⁵ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
²⁶ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands.
²⁷ Icelandic Heart Association, Holtasmari 1, Kopavogur IS-201, Iceland.
²⁸ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
²⁹ Indiana University, Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA.
³⁰ Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
³¹ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0SL, UK.
³² Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal DE-14558, Germany.
³³ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas 77225, USA.
³⁴ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, USA.
³⁵ 1] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam 2300 RC, The Netherlands.
³⁶ Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm SE-171 77, Sweden.
³⁷ 1] Icelandic Heart Association, Holtasmari 1, Kopavogur IS-201, Iceland [2] University of Iceland, Reykjavik IS-101, Iceland.
³⁸ 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
³⁹ Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
⁴⁰ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital, Malmö SE-205 02, Sweden.
⁴¹ 1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [2] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore.
⁴² Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano 20132, Italy.
⁴³ 1] Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Maryland 21205, USA [2] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
⁴⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁴⁵ Section of Biology and Genetics, Department of Life and Reproduction Sciences, University of Verona, Verona 37100, Italy.
⁴⁶ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
⁴⁷ Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁴⁸ 1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [2] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore [3] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 119228, Singapore [4] Office of Clinical Sciences, Duke-NUS Graduate Medical School, National University of Singapore, Singapore 169857, Singapore.
⁴⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
⁵⁰ Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands.
⁵¹ 1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA [2] Division of Cardiology, Geneva University Hospital Geneva 1211, Switzerland.
⁵² Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece.
⁵³ 1] Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm SE-171 77, Sweden [2] Department of Numerical Analysis and Computer Science, SciLifeLab, Stockholm University, Stockholm SE-106 91, Sweden.
⁵⁴ Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Catholic University, Rome 00168, Italy.
⁵⁵ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
⁵⁶ Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, USA.
⁵⁷ Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁵⁸ The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
⁵⁹ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala SE-751 85, Sweden.
⁶⁰ Department of Biobank Research, Umeå University, Umeå SE-901 87, Sweden.
⁶¹ Department of Biomedical Technology, Sangmyung University, Chungnam 330-720, Korea.
⁶² 1] Institute of Human Genetics, Department of Genomics, Life &Brain Center, University of Bonn, Bonn DE-53127, Germany [2] Human Genomics Research Group, Division of Medical Genetics, University Hospital Basel Department of Biomedicine 4031, Basel, Switzerland [3] Institute of Neuroscience and Medicine (INM-1) Genomic Imaging Research Center Juelich, Juelich DE-52425, Germany.
⁶³ 1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [2] Office of Clinical Sciences, Duke-NUS Graduate Medical School, National University of Singapore, Singapore 169857, Singapore [3] Memory Aging &Cognition Centre (MACC), National University Health System, Singapore 117599, Singapore.
⁶⁴ Steno Diabetes Center, Gentofte DK-2820, Denmark.
⁶⁵ 1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup DK-2600, Denmark [2] Faculty of Medicine, University of Aalborg, Aalborg DK-9220, Denmark.
⁶⁶ Echinos Medical Centre, Echinos 67300, Greece.
⁶⁷ 1] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore [2] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 119228, Singapore [3] Division of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
⁶⁸ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio FI-70211, Finland.
⁶⁹ 1] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁷⁰ 1] Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan [2] School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
⁷¹ Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
⁷² National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA.
⁷³ Department of Epidemiology &Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina 27106, USA.
⁷⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁷⁵ 1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup DK-2600, Denmark [2] Department of Clinical Experimental Research, Copenhagen University Hospital Glostrup, Glostrup DK-2600, Denmark [3] Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
⁷⁶ 1] National and Kapodistrian University of Athens, Faculty of Medicine, Athens 115 27, Greece [2] Dromokaiteio Psychiatric Hospital, Athens 124 61, Greece.
⁷⁷ 1] Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland 21205, USA.
⁷⁸ The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
⁷⁹ Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles 90033, USA.
⁸⁰ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
⁸¹ 1] Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece [2] University of Leicester, Leicester LE1 7RH, UK.
⁸² 1] Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA [2] Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27106, USA.
⁸³ 1] Department of Internal Medicine, Division of Endocrinology, Metabolism, Pathobiochemistry and Clinical Chemistry and Institute of Diabetes Research and Metabolic Diseases, University of Tübingen, Tübingen DE-72076, Germany [2] German Center for Diabetes Research (DZD), Neuherberg DE-85764, Germany.
⁸⁴ 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK [3] The Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
⁸⁵ 1] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA [2] Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA.
⁸⁶ 1] Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm SE-171 77, Sweden [2] Science for Life Laboratory, Karolinska Institutet, Stockholm SE-171 77, Sweden.
⁸⁷ Department of Gastroenterology, Gennimatas General Hospital, Athens 11527, Greece.
⁸⁸ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁸⁹ 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Hematology, Long Road, Cambridge CB2 0XY, UK.
⁹⁰ Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁹¹ Division of Psychiatric Genomics, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
⁹² 1] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK.
⁹³ First Department of Propaedeutic and Internal Medicine, Athens University Medical School, Laiko General Hospital, Athens 11527, Greece.
⁹⁴ Diabetes Centre, 2nd Department of Internal Medicine, National University of Athens, Hippokration General Hospital, Athens 11527, Greece.
⁹⁵ Anogia Medical Centre, Anogia 740 51, Greece.
⁹⁶ The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
⁹⁷ 1] Dromokaiteio Psychiatric Hospital, Athens 124 61, Greece [2] University of Sheffield, Sheffield S10 2TN, UK.
⁹⁸ 1] Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [2] Department of Statistics, University of California at Berkeley, Berkeley, California 94720, USA.
⁹⁹ 1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
¹⁰⁰ 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark [2] Faculty of Health Science, University of Copenhagen, Copenhagen 1165, Denmark.
¹⁰¹ 1] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala SE-751 85, Sweden [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
¹⁰² Division of Research, Kaiser Permanente, Northern California Region, Oakland, California 94612, USA.
¹⁰³ Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 77030, USA.
¹⁰⁴ Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado 80204, USA.
¹⁰⁵ 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹⁰⁶ 1] Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan [2] School of Medicine, National Yang-Ming University, Taipei 112, Taiwan [3] College of Medicine, National Defense Medical Center, Taipei 114, Taiwan.
¹⁰⁷ Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27106, USA.
¹⁰⁸ Department of Epidemiology, German Institute of Human Nutrition Potsdam Rehbrücke, Nuthetal DE-14558, Germany.
¹⁰⁹ 1] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK [2] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK [3] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah 22254, Saudi Arabia.
¹¹⁰ CNR Institute of Clinical Physiology, Pisa 73100, Italy.
¹¹¹ 1] Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital, Malmö SE-205 02, Sweden [2] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA [3] Department of Public Health &Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden.
¹¹² Genetics of Diabetes, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
¹¹³ MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland EH4 2XU, UK.
¹¹⁴ 1] Department of Public Health &Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden [2] Research Unit, Skellefteå SE-931 87, Sweden.
¹¹⁵ 1] Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Framingham Heart Study, Framingham, Massachusetts 01702, USA.
¹¹⁶ 1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts 01702, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
¹¹⁷ 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, Cambridge CB2 1TN, UK.
¹¹⁸ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
¹¹⁹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, USA.
¹²⁰ Department of Public Health, Faculty of Medicine, University of Split, Split 21000, Croatia.
¹²¹ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22908, USA.
¹²² 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] Division of Cardiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
¹²³ Centre for Population Health Sciences, Medical School, University of Edinburgh, Edinburgh, Scotland EH8 9YL, UK.
¹²⁴ 1] Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal DE-14558, Germany [2] German Center for Diabetes Research (DZD), Neuherberg DE-85764, Germany.
¹²⁵ Medical Research Institute, University of Dundee, Dundee DD1 9SY, UK.
¹²⁶ 1] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands.
¹²⁷ Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK.
¹²⁸ 1] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [2] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119228, Singapore [3] Office of Clinical Sciences, Duke-NUS Graduate Medical School, National University of Singapore, Singapore 169857, Singapore.
¹²⁹ 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA [2] Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹³⁰ 1] Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA [3] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA [4] Department of Health Services, University of Washington, Seattle, Washington 98195, USA [5] Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98195, USA.
¹³¹ 1] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 119228, Singapore [2] Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
¹³² 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CE, The Netherlands [2] Center for Medical Systems Biology, Leiden 2300, The Netherlands.
¹³³ Genetics, PCPS, GlaxoSmithKline, Philadelphia, Pennsylvania 19104, USA.
¹³⁴ 1] Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas 77225, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
¹³⁵ 1] Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21205, USA [2] Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland 21205, USA [3] Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
¹³⁶ 1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA [4] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
¹³⁷ 1] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹³⁸ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 38677, USA.
¹³⁹ 1] New York Academy of Medicine, New York, New York 10029, USA [2] Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington 98195, USA.
¹⁴⁰ 1] Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA [2] Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

PMID: 25631608
PMCID: PMC4311266
DOI: 10.1038/ncomms6897

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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Conflict of interest statement

J.C.F. has received consulting honoraria from PanGenX and Pfizer; T.F. consulted for Boeringer Ingelheim; J.B.M. serves as a consultant to LipoScience, and Quest Diagnostics; B.P. serves on the DSMB of a clinical trial for a device funded by the manufacturer (Zoll LifeCor) and on the Steering Committee for the Yale Open Data Access Project funded by Johnson & Johnson; D.M.W., M.G.E., L.L. and J.A. are all full time employees of GlaxoSmithKline. P.M.R. and D.I.C. have research grant support from Amgen, AstraZeneca and the NHLBI. The remaining authors declare no competing financial interests.

Figures

**Figure 1. Glycaemic associations with rs10305492 (*GLP1R* A316T).**
Glycaemic phenotypes were tested for association with rs10305492 in *GLP1R* (A316T). Each phenotype, sample size (N), covariates in each model, beta per s.d., 95% confidence interval (95%CI) and P values (P) are reported. Analyses were performed on native distributions and scaled to s.d. values from the Fenland or Ely studies to allow comparisons of effect sizes across phenotypes.

**Figure 2. *GLP1R* regional association plot.**
Regional association results (−log₁₀p) for fasting glucose of *GLP1R* locus on chromosome 6. Linkage disequilibrium (r²) indicated by colour scale legend. Triangle symbols indicate variants with MAF>5%, square symbols indicate variants with MAF1–5% and circle symbols indicate variants with MAF<1%.

**Figure 3. G6PC2.**
(a) Regional association results (−log₁₀p) for fasting glucose of the *G6PC2* locus on chromosome 2. Minor allele frequencies (MAF) of common and rare *G6PC2* SNVs from single-variant analyses are shown. P values for rs560887, rs563694 and rs552976 were artificially trimmed for the figure. Linkage disequilibrium (r²) indicated by colour scale legend. y-Axis scaled to show associations for variant rs560887 (purple dot, MAF=43%, P=4.2 × 10⁻⁸⁷). Triangle symbols indicate variants with MAF>5%, square symbols indicate variants with MAF1–5% and circle symbols indicate variants with MAF <1%. (b) Regional association results (−log₁₀p) for fasting glucose conditioned on rs560887 of *G6PC2*. After adjustment for rs560887, both rare SNVs rs2232326 (S324P) and rs146779637 (R283X), and common SNV rs492594 remain significantly associated with FG indicating the presence of multiple independent associations with FG at the *G6PC2* locus. (c) Inset of *G6PC2* gene with depiction of exon locations, amino-acid substitutions and MAFs of the 15 SNVs included in gene-based analysis (MAF<1% and nonsynonymous, splice-site and gain/loss-of-function variation types as annotated by dbNSFPv2.0). (d) The contribution of each variant on significance and effect of the SKAT test when one variant is removed from the test. Gene-based SKAT P values (blue line) and test statistic (red line) of *G6PC2* after removing one SNV at a time and re-calculating the association. (e) Haplotypes and haplotype association statistics and P values generated from the 15 rare SNVs from gene-based analysis of *G6PC2* from 18 cohorts and listed in panel (c). Global haplotype association, P=1.1 × 10⁻¹⁷. Haplotypes ordered by decreasing frequency with haplotype 1 as the reference. Orange highlighting indicates the minor allele of the SNV on the haplotype.

See this image and copyright information in PMC

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

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

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