Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
37679419
TITLE
GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.
ABSTRACT
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
© 2023. The Author(s).
DATE PUBLISHED
2023 Sep
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2021/09/18
accepted 2023/06/27
medline 2023/09/11 06:43
pubmed 2023/09/08 00:41
entrez 2023/09/07 23:26
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Lagou V Lagou Vasiliki V VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium.
Jiang L Jiang Longda L Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Ulrich A Ulrich Anna A Department of Clinical and Experimental Medicine, School of Biosciences and Medicine, University of Surrey, Guildford, UK.
Zudina L Zudina Liudmila L Department of Clinical and Experimental Medicine, School of Biosciences and Medicine, University of Surrey, Guildford, UK.
González KSG González Karla Sofia Gutiérrez KSG Department of Molecular Diagnostics, Clinical Laboratory, Clinica Biblica Hospital, San José, Costa Rica.
Balkhiyarova Z Balkhiyarova Zhanna Z People-Centred Artificial Intelligence Institute, University of Surrey, Guildford, UK.
Faggian A Faggian Alessia A Laboratory for Artificial Biology, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
Maina JG Maina Jared G JG UMR 8199-EGID, Institut Pasteur de Lille, CNRS, University of Lille, Lille, France.
Chen S Chen Shiqian S Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.
Todorov PV Todorov Petar V PV Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Sharapov S Sharapov Sodbo S MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia.
David A David Alessia A Centre for Bioinformatics and System Biology, Department of Life Sciences, Imperial College London, London, UK.
Marullo L Marullo Letizia L Department of Evolutionary Biology, Genetic Section, University of Ferrara, Ferrara, Italy.
Mägi R Mägi Reedik R Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Rujan RM Rujan Roxana-Maria RM Centre for Sports, Exercise and Life Sciences, Coventry University, Conventry, UK.
Ahlqvist E Ahlqvist Emma E Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Thorleifsson G Thorleifsson Gudmar G deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
Gao Η Gao Ηe ? Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Εvangelou Ε Εvangelou Εvangelos ? Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
Benyamin B Benyamin Beben B South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
Scott RA Scott Robert A RA MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Isaacs A Isaacs Aaron A Department of Physiology, Maastricht University, Maastricht, the Netherlands.
Zhao JH Zhao Jing Hua JH Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Willems SM Willems Sara M SM Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Johnson T Johnson Toby T Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Gieger C Gieger Christian C German Center for Diabetes Research (DZD), Neuherberg, Germany.
Grallert H Grallert Harald H German Center for Diabetes Research (DZD), Neuherberg, Germany.
Meisinger C Meisinger Christa C Epidemiology, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
Müller-Nurasyid M Müller-Nurasyid Martina M Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Strawbridge RJ Strawbridge Rona J RJ School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
Goel A Goel Anuj A Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Rybin D Rybin Denis D Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Albrecht E Albrecht Eva E Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Jackson AU Jackson Anne U AU Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
Stringham HM Stringham Heather M HM Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
Corrêa IR Jr Corrêa Ivan R IR New England Biolabs, Ipswich, MA, USA.
Farber-Eger E Farber-Eger Eric E Vanderbilt Institute for Clinical and Translational Research and Vanderbilt Translational and Clinical Cardiovascular Research Center, Nashville, TN, USA.
Steinthorsdottir V Steinthorsdottir Valgerdur V deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
Uitterlinden AG Uitterlinden André G AG Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
Munroe PB Munroe Patricia B PB NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Brown MJ Brown Morris J MJ Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Schmidberger J Schmidberger Julian J Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany.
Holmen O Holmen Oddgeir O Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway.
Thorand B Thorand Barbara B German Center for Diabetes Research (DZD), Neuherberg, Germany.
Hveem K Hveem Kristian K K G Jebsen Centre for Genetic Epdiemiology, Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway.
Wilsgaard T Wilsgaard Tom T Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
Mohlke KL Mohlke Karen L KL Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Wang Z Wang Zhe Z The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
GWA-PA Consortium
Shmeliov A Shmeliov Aleksey A Department of Clinical and Experimental Medicine, School of Biosciences and Medicine, University of Surrey, Guildford, UK.
den Hoed M den Hoed Marcel M The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden.
Loos RJF Loos Ruth J F RJF The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Kratzer W Kratzer Wolfgang W Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany.
Haenle M Haenle Mark M Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany.
Koenig W Koenig Wolfgang W Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
Boehm BO Boehm Bernhard O BO Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore and Department of Endocrinology, Tan Tock Seng Hospital, Singapore City, Singapore.
Tan TM Tan Tricia M TM Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.
Tomas A Tomas Alejandra A Section of Cell Biology and Functional Genomics, Imperial College London, London, UK.
Salem V Salem Victoria V Department of Bioengineering, Imperial College London, South Kensington Campus, London, UK.
Barroso I Barroso Inês I Exeter Centre of Excellence for Diabetes Research (EXCEED), University of Exeter Medical School, Exeter, UK.
Tuomilehto J Tuomilehto Jaakko J Diabetes Research Unit, King Abdulaziz University, Jeddah, Saudi Arabia.
Boehnke M Boehnke Michael M Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
Florez JC Florez Jose C JC Department of Medicine, Harvard Medical School, Boston, MA, USA.
Hamsten A Hamsten Anders A Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.
Watkins H Watkins Hugh H Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Njølstad I Njølstad Inger I Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
Wichmann HE Wichmann H-Erich HE Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Caulfield MJ Caulfield Mark J MJ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Khaw KT Khaw Kay-Tee KT Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
van Duijn CM van Duijn Cornelia M CM Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Hofman A Hofman Albert A Netherlands Consortium for Healthy Ageing, the Hague, the Netherlands.
Wareham NJ Wareham Nicholas J NJ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Langenberg C Langenberg Claudia C Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
Whitfield JB Whitfield John B JB QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Montgomery G Montgomery Grant G Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia.
Scapoli C Scapoli Chiara C Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
Tzoulaki I Tzoulaki Ioanna I Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
Elliott P Elliott Paul P National Institute for Health Research Imperial College London Biomedical Research Centre, Imperial College London, London, UK.
Thorsteinsdottir U Thorsteinsdottir Unnur U Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
Stefansson K Stefansson Kari K Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
Brittain EL Brittain Evan L EL Vanderbilt University Medical Center and the Vanderbilt Translational and Clinical Cardiovascular Research Center, Nashville, TN, USA.
McCarthy MI McCarthy Mark I MI Genentech, South San Francisco, CA, USA.
Froguel P Froguel Philippe P UMR 8199-EGID, Institut Pasteur de Lille, CNRS, University of Lille, Lille, France.
Sexton PM Sexton Patrick M PM ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Wootten D Wootten Denise D ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Groop L Groop Leif L Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland.
Dupuis J Dupuis Josée J Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.
Meigs JB Meigs James B JB Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
Deganutti G Deganutti Giuseppe G Centre for Sports, Exercise and Life Sciences, Coventry University, Conventry, UK.
Demirkan A Demirkan Ayse A Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
Pers TH Pers Tune H TH Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Reynolds CA Reynolds Christopher A CA School of Life Sciences, University of Essex, Colchester, UK.
Aulchenko YS Aulchenko Yurii S YS MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia.
Kaakinen MA Kaakinen Marika A MA People-Centred Artificial Intelligence Institute, University of Surrey, Guildford, UK. m.kaakinen@imperial.ac.uk.
Jones B Jones Ben B Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK. ben.jones@imperial.ac.uk.
Prokopenko I Prokopenko Inga I UMR 8199-EGID, Institut Pasteur de Lille, CNRS, University of Lille, Lille, France. i.prokopenko@surrey.ac.uk.
Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC)
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
den Hoed Marcel M
van Duijn Cornelia M CM
JOURNAL
VOLUME: 55
ISSUE: 9
TITLE: Nature genetics
ISOABBREVIATION: Nat Genet
YEAR: 2023
MONTH: Sep
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1546-1718
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nat Genet
COUNTRY: United States
ISSNLINKING: 1061-4036
NLMUNIQUEID: 9216904
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
Wellcome Trust United Kingdom
R01 DK072193 NIDDK NIH HHS United States
U01 DK105535 NIDDK NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Humans
Glucose
Genome-Wide Association Study
Blood Glucose genetics
Diabetes Mellitus, Type 2 genetics
Colon genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
IY9XDZ35W2 Glucose
0 Blood Glucose
OTHER ID's
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