Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization
Wellcome Open Research, vol. 8, pp. 483
Abstract
Background: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods: To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results: Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.
Authors 100
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University of Cambridge · MRC Epidemiology Unit · Saarland University
Affiliation as printed
General Medicine Center, Saarland University Faculty of Medicine, Homburg, 66421, Germany
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
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Agency for Science, Technology and Research · University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism · Institute of Molecular and Cell Biology
Affiliation as printed
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LE, UK
Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore
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Centre for Human Genetics · University of Oxford
Affiliation as printed
Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
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Broad Institute · Boston Children's Hospital · Harvard University · Vertex Pharmaceuticals (United States)
Affiliation as printed
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Current address: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA, 02210, USA
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02115, USA
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University of Cambridge · Wellcome Sanger Institute · MRC Epidemiology Unit
Affiliation as printed
Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
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Broad Institute · Massachusetts General Hospital · Indiana University Indianapolis · Indiana University School of Medicine
Affiliation as printed
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Departments of Epidemiology & Medicine, Schools of Public Health & Medicine, Indiana University, Indianapolis, IN, 46202, USA
Diabetes Translational Research Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
General Medicine Division, Massachusetts General Hospital, Boston, MA, USA
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Centre for Human Genetics · University of Oxford
Affiliation as printed
Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
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Affiliation as printed
Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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National University of Singapore · University of Michigan · National University Health System
Affiliation as printed
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore, 117549, Singapore
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Affiliation as printed
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK
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Affiliation as printed
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
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Affiliation as printed
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
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Boston University · The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
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Boston University · The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
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Affiliation as printed
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden
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University of Cambridge · Wellcome Sanger Institute · MRC Biostatistics Unit
Affiliation as printed
Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK
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Affiliation as printed
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
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Karolinska Institutet · University of Glasgow
Affiliation as printed
Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, 171 76, Sweden
Mental Health and Wellbeing, School of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8RZ, UK
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Wayne State University · McGill University
Affiliation as printed
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201-1928, USA
Quantitative Life Sciences, McGill University, Montreal, Quebec, Canada
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University of Copenhagen · Gentofte Hospital · Copenhagen Prospective Studies on Asthma in Childhood · Steno Diabetes Center Copenhagen
Affiliation as printed
COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
Steno Diabetes Center Copenhagen, Gentofte, 2820, Denmark
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Washington University in St. Louis
Affiliation as printed
Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, 63108, USA
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Oulu University Hospital · University of Oulu
Affiliation as printed
Center for Life Course Health Research, University of Oulu, Oulu, 90014, Finland
Unit of Primary Care, Oulu University Hospital, Oulu, Finland
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Affiliation as printed
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
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Affiliation as printed
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
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Affiliation as printed
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, USA
Department of Medicine, University of Washington, Seattle, WA, USA
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Institute of Genetics and Cancer · University of Edinburgh
Affiliation as printed
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK
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Affiliation as printed
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA
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Affiliation as printed
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
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Affiliation as printed
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015 GE, The Netherlands
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Affiliation as printed
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, USA
Department of Medicine, University of Washington, Seattle, WA, USA
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Affiliation as printed
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA
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The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
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Uppsala University · Science for Life Laboratory
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Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, 75237, Sweden
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Affiliation as printed
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
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Affiliation as printed
Icelandic Heart Association, Kopavogur, Iceland
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MRC Centre for Environment and Health · Imperial College London · University of Oulu
Affiliation as printed
Biocenter Oulu, University of Oulu, Oulu, Finland
Center for Life Course Health Research, University of Oulu, Oulu, 90014, Finland
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, W2 1PG, UK
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Affiliation as printed
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, USA
Department of Medicine, University of Washington, Seattle, WA, USA
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Queen Mary University of London · William Harvey Research Institute
Affiliation as printed
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Oulu University Hospital · University of Oulu
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Faculty of Medicine, Center for Life Course Health Research, University of Oulu, Oulu, Finland
MRC and Unit of Primary Care, Oulu University Hospital, Oulu, Finland
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Johns Hopkins University · University of Utah
Affiliation as printed
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Division of Nephrology, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, USA
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Vanderbilt University · Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Medicine, Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY, 10069, USA
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University of Cambridge · MRC Epidemiology Unit
Affiliation as printed
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
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Harvard University · Massachusetts General Hospital
Affiliation as printed
Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, 02114, USA
Department of Medicine, Harvard Medical School, Boston, MA, USA
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Institute of Genetics and Cancer · MRC Human Genetics Unit · University of Edinburgh
Affiliation as printed
Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK
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German Center for Diabetes Research · German Institute of Human Nutrition
Affiliation as printed
Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany
German Center for Diabetes Research (DZD), München-Neuherberg, 85764, Germany
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Dennis O. Mook‐Kanamori Aachen Department of Clinical Epidemiology Department of Public Health and Primary Care
Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
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University of Bern · Erasmus MC
Affiliation as printed
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015 GE, The Netherlands
Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
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University of Michigan · Institute of Genetic and Biomedical Research · National Research Council
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Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
Italian National Research Council, Institute of Genetics and Biomedic Research, Cittadella Universitaria, Monserrato, 09042, Italy
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Affiliation as printed
Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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Affiliation as printed
Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, USA
Department of Biostatistics, University of Washington, Seattle, WA, USA
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University Medical Center Groningen · University of Groningen · Institute of Genetic and Biomedical Research · National Research Council
Affiliation as printed
Italian National Research Council, Institute of Genetics and Biomedic Research, Cittadella Universitaria, Monserrato, 09042, Italy
University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, 9700 RB, The Netherlands
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University of Iceland · Icelandic Heart Association
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Faculty of Medicine, University of Iceland, Reykjavik, Iceland
Icelandic Heart Association, Kopavogur, Iceland
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University of Michigan · Institute for Social Research
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Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA
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Centre for Human Genetics · Wellcome Sanger Institute · Helmholtz Munich · University of Oxford
Affiliation as printed
Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
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Affiliation as printed
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, 3584CX, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Queen Mary University of London · William Harvey Research Institute
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Barts Cardiovascular Research Unit, Barts and The London School of Medicine & Dentistry, Queen Mary University, London, EC1M 6BQ, UK
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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The Lundquist Institute · Harbor–UCLA Medical Center
Affiliation as printed
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
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Imperial College London · Brunel University of London
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Department of Life Sciences, Brunel University London, London, UB8 3PH, UK
Section of Investigative Medicine, Department of Medicine, Imperial College London, London, W12 0NN, UK
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Ealing Hospital · London North West Healthcare NHS Trust · Imperial College London
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Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK
Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK
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Affiliation as printed
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
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University of North Carolina at Chapel Hill
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Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA
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University of North Carolina at Chapel Hill · The University of Texas Health Science Center at Houston
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Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA
Human Genetics Center, The University of Texas School of Public Health; The University of Texas Graduate School of Biomedical Sciences at Houston;, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
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University of North Carolina at Chapel Hill
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Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA
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Queen Mary University of London · William Harvey Research Institute
Affiliation as printed
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Affiliation as printed
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015 GE, The Netherlands
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, 3015 GE, The Netherlands
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MRC Centre for Environment and Health · Imperial College London
Affiliation as printed
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, W2 1PG, UK
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Queen Mary University of London · King Abdulaziz University · William Harvey Research Institute
Affiliation as printed
Department of Medicine, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Affiliation as printed
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015 GE, The Netherlands
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Health Data Research UK · Amsterdam University Medical Centers · University College London · University of Amsterdam
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Amsterdam University Medical Centers, Department of Cardiology, University of Amsterdam, Amsterdam, The Netherlands
Health Data Research UK and Institute of Health Informatics, University College London, London, UK
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National Institutes of Health · National Human Genome Research Institute
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Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA
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University Medical Center Utrecht
Affiliation as printed
Center for Circulatory Health, University Medical Center Utrecht, Utrecht, 3508GA, The Netherlands
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University of Southern Denmark · Vejle Sygehus · Lillebaelt Hospital
Affiliation as printed
Department of Clinical Biochemistry, Lillebaelt Hospital Vejle, Vejle, 7100, Denmark
Institute of Regional Health Research, University of Southern Denmark, Odense, 5000, Denmark
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Affiliation as printed
Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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Affiliation as printed
Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB18RN, UK
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
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Erasmus MC · UK Dementia Research Institute · MRC Centre for Environment and Health · Imperial College London
Affiliation as printed
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, W2 1PG, UK
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015 GE, The Netherlands
UK Dementia Research Institute, Imperial College London, London, UK
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Affiliation as printed
Oulu University Hospital, Oulu, 90220, Finland
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NIHR Imperial Biomedical Research Centre · Health Data Research UK · MRC Centre for Environment and Health · Imperial College London
Affiliation as printed
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, W2 1PG, UK
Health Data Research UK, Imperial College London, London, UK
Imperial College NIHR Biomedical Research Centre, London, UK
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Harokopio University of Athens · University College London
Affiliation as printed
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, 17671, Greece
Department of Population Science and Experimental Medicine, Institute of Cardiovascular Science, University College London, London, UK
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University of Michigan · Institute for Social Research
Affiliation as printed
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA
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Boston Children's Hospital · Harvard University · Lund University
Affiliation as printed
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden
Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02115, USA
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Affiliation as printed
Institute of Reproductive and Developmental Biology, Imperial College London, London, W12 0NN, UK
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Universitätsklinikum Tübingen · German Center for Diabetes Research · University of Tübingen
Affiliation as printed
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry, University Hospital of Tübingen, Tübingen, Germany
German Center for Diabetes Research (DZD), München-Neuherberg, 85764, Germany
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University of Copenhagen · Novo Nordisk Foundation Center for Basic Metabolic Research
Affiliation as printed
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
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Affiliation as printed
Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
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University of Iceland · Icelandic Heart Association
Affiliation as printed
Faculty of Medicine, University of Iceland, Reykjavik, Iceland
Icelandic Heart Association, Kopavogur, Iceland
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Affiliation as printed
Department of Biobank Research, Umeå University, Umeå, SE-901 87, Sweden
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Affiliation as printed
Icelandic Heart Association, Kopavogur, Iceland
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Poznan University of Medical Sciences · Oulu University Hospital
Affiliation as printed
Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, 60-572, Poland
Institute of Biomedicine and Biocenter of Oulu, Faculty of Medicine, Medical Research Center Oulu and Oulu University Hospital, Oulu, Finland
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Harvard University · Massachusetts General Hospital · Harvard Pilgrim Health Care
Affiliation as printed
Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA
Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
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University of Copenhagen · Frederiksberg Hospital · Bispebjerg Hospital · Aalborg University
Affiliation as printed
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, 2000, Denmark
Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
Faculty of Medicine, University of Aalborg, Aalborg, 9100, Denmark
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University of Southern Denmark · Steno Diabetes Center Copenhagen
Affiliation as printed
National Institute of Public Health, Southern Denmark University, Odense, 5000, Denmark
Steno Diabetes Center Copenhagen, Gentofte, 2820, Denmark
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Finnish Institute for Health and Welfare
Affiliation as printed
Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, FI-00271, Finland
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