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GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

  • Vasiliki Lagou
  • , Longda Jiang
  • , Anna Ulrich
  • , Liudmila Zudina
  • , Karla Sofia Gutiérrez González
  • , Zhanna Balkhiyarova
  • , Alessia Faggian
  • , Jared G Maina
  • , Shiqian Chen
  • , Petar V Todorov
  • , Sodbo Sharapov
  • , Alessia David
  • , Letizia Marullo
  • , Reedik Mägi
  • , Roxana-Maria Rujan
  • , Emma Ahlqvist
  • , Gudmar Thorleifsson
  • , Ηe Gao
  • , Εvangelos Εvangelou
  • , Beben Benyamin
    • Robert A Scott, Aaron Isaacs, Jing Hua Zhao, Sara M Willems, Toby Johnson, Christian Gieger, Harald Grallert, Christa Meisinger, Martina Müller-Nurasyid, Rona J Strawbridge, Anuj Goel, Denis Rybin, Eva Albrecht, Anne U Jackson, Heather M Stringham, Ivan R Corrêa Jr., Eric Farber-Eger, Valgerdur Steinthorsdottir, André G Uitterlinden, Patricia B Munroe, Morris J Brown, Julian Schmidberger, Oddgeir Holmen, Barbara Thorand, Kristian Hveem, Tom Wilsgaard, Karen L Mohlke, Zhe Wang, GWA-PA Consortium, Aleksey Shmeliov, Marcel den Hoed, Ruth J. F. Loos, Wolfgang Kratzer, Haenle Mark, Wolfgang Koenig, Bernhard O Boehm, Tricia M. Tan, Alejandra Tomas, Victoria Salem, Inês Barroso, Jaakko Tuomilehto, Michael Boehnke, Jose C Florez, Anders Hamsten, Hugh Watkins, Inger Njølstad, H-Erich Wichmann, Mark J Caulfield, Kay Tee Khaw, Cornelia M van Duijn, Albert Hofman, Nicholas J. Wareham, Claudia Langenberg, John B Whitfield, Nicholas G Martin, Grant Montgomery, Chiara Scapoli, Ioanna Tzoulaki, Paul Elliott, Unnur Thorsteinsdottir, Kari Stefansson, Evan L Brittain, Mark I. McCarthy, Philippe Froguel, Patrick M Sexton, Denise L Wootten, Leif Groop, Josée Dupuis, James B Meigs, Giuseppe Deganutti, Ayse Demirkan, Tune H Pers, Chris Reynolds, Yurii S Aulchenko, Marika A Kaakinen, Ben J. Jones, Inga Prokopenko, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)
    • University of Queensland
    • Erasmus University Medical Center
    • University of Surrey
    • Institute of Cytology and Genetics
    • University of Ferrara
    • University of Tartu
    • Amgen
    • Queen Mary University of London
    • University of Augsburg
    • Karolinska Institutet
    • New England Biolabs
    • Vanderbilt University
    • Ulm University Medical Centre
    • Norwegian University of Science and Technology
    • University of Tromsø
    • University of Oxford
    • VIB-KU Leuven Center for Brain & Disease Research
    • Imperial College London
    • Clinica Biblica Hospital
    • Universita di Trento
    • University of Lille
    • University of Copenhagen
    • Moscow State University
    • Lund University
    • University of Ioannina
    • University of South Australia
    • South Australian Health and Medical Research Institute
    • Maastricht University
    • German Research Center for Environmental Health
    • German Center for Diabetes Research (DZD)
    • Johannes Gutenberg University of Mainz
    • Ludwig Maximilian University of Munich
    • Karolinska University Hospital
    • University of Glasgow
    • University of Michigan
    • University of North Carolina
    • Icahn School of Medicine at Mount Sinai
    • Institute of Epidemiology
    • Uppsala University
    • Finnish Institute for Health and Welfare
    • University of Helsinki
    • King Abdulaziz University
    • Netherlands Consortium for healthy ageing
    • Charite University hospital
    • Wellcome Trust Sanger Institute
    • University of Ulm
    • Technical University of Munich
    • DZHK (German Centre for Cardiovascular Research)
    • University of Exeter
    • Massachusetts General Hospital
    • Broad Institute
    • Harvard Medical School
    • QIMR Berghofer Medical Research Institute
    • University of Iceland
    • McGill University
    • University Medical Center Groningen
    • University of Essex
    • Monash University
    • Nanyang Technological University
    • Tan Tock Seng Hospital
    • Leiden University
    • University of Cambridge
    • Boston University
    • Boston University School of Public Health

    Research output: Contribution to journal › Article › peer-review

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    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.

    Original languageEnglish
    Pages (from-to)1448-1461
    Number of pages14
    JournalNature Genetics
    Volume55
    Issue number9
    DOIs
    Publication statusPublished - 7 Sept 2023

    Bibliographical note

    This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

    Funder

    We are supported by the following: the Medical Research Council (grants MR/L01341X/1 to P.E., MR/R010676/1 to B.J., MR/R010676/1 to A.T.); PHE (to P.E.); the UK Dementia Research Institute (to P.E. and I.T.); the Alzheimer’s Society (to P.E. and I.T.); the Alzheimer’s Research UK (to P.E. and I.T.); the National Health and Medical Research Council (NHMRC) Fellowship Schemes (552498 to B.B., 339446 and 619667 to G.M.); the NHMRC Ideas (grant 1184726 to P.M.S. and D.W.); the NHMRC (grants 1150083 to P.M.S. and D.W., 1154434 to P.M.S., 1155302 to D.W.); the Swedish Research Council (grants 2017-02688, 2020-02191 to E. Ahlqvist and 2019-01417 to M.d.H.); the Swedish Heart-Lung Foundation (grants 20200781 and 20200602 to M.d.H.); the British Heart Foundation (to A.G.), the European Commission (grants LSHM-CT-2007-037273 and HEALTH-F2-2013-601456 to A.G.); the Novo Nordisk Foundation (grants NNF15CC0018486 to A.G. and NNF18CC0034900 to T.H.P.); the Lundbeck Foundation (grant R190-2014-3904 to T.H.P.); VIAgenomics (grant SP/19/2/344612 to A.G.); the Wellcome Trust (grants 090532/Z/09/Z, 203141/Z/16/Z to H.W., 104955/Z/14/Z to A. David, 090532 to M.I.M., 098381 to M.I.M., 106130 to M.I.M., 203141 to M.I.M., 212259 to M.I.M., 205915/Z/17/Z to I.P.); UKRI Innovation-HDR-UK Fellowship (grant MR/S003061/1 to R.J.S.); European Union’s Horizon 2020 research and innovation program LONGITOOLS (grant H2020-SC1-2019-874739 to M.A.K., A.U., Z.B. and I.P.); the European Foundation for the Study of Diabetes (to B.J. and M.A.K.); the Imperial Post-CCT Post-Doctoral Fellowship (to B.J.); the Academy of Medical Sciences (to B.J.); the National Institute for Health Research Imperial NIHR Biomedical Research Center (to B.J. and T.M.T.); the Engineering and Physical Sciences Research Council (to B.J.); the Society for Endocrinology (to B.J.); the British Society for Neuroendocrinology (to B.J.); Research England ‘Expanding excellence in England’ (to I.B.); the Research Foundation-Flanders (to V.L.); the Diabetes UK (to V. Salem, A.T.; BDA, 20/0006307 to I.P.); the Russian Science Foundation (grant 19-15-00115 to S.S.); the NIDDK (grant U01-DK105535 to M.I.M.); European Federation for the Study of Diabetes (to A.T.); the Agence Nationale de la Recherche (PreciDIAB, grant ANR-18-IBHU-0001 to J.G.M. and I.P.); the University of Lille mobility grant (to J.G.M.); the People-Centered Artificial Intelligence Institute, University of Surrey (Z.B., M.A.K., A. Demirkan and I.P.); the World Cancer Research Fund (to I.P.); the World Cancer Research Fund International (grant 2017/1641 to I.P.); the Royal Society (grant IEC\R2\181075 to I.P. and C.A.R.); the European Union through the ‘Fonds européen de développement regional’ (FEDER; to I.P.); the ‘Conseil Régional des Hauts-de-France’ (Hauts-de-France Regional Council; to I.P.); the ‘Métropole Européenne de Lille’ (MEL, European Metropolis of Lille; to I.P.).

    Funding

    We are supported by the following: the Medical Research Council (grants MR/L01341X/1 to P.E., MR/R010676/1 to B.J., MR/R010676/1 to A.T.); PHE (to P.E.); the UK Dementia Research Institute (to P.E. and I.T.); the Alzheimer’s Society (to P.E. and I.T.); the Alzheimer’s Research UK (to P.E. and I.T.); the National Health and Medical Research Council (NHMRC) Fellowship Schemes (552498 to B.B., 339446 and 619667 to G.M.); the NHMRC Ideas (grant 1184726 to P.M.S. and D.W.); the NHMRC (grants 1150083 to P.M.S. and D.W., 1154434 to P.M.S., 1155302 to D.W.); the Swedish Research Council (grants 2017-02688, 2020-02191 to E. Ahlqvist and 2019-01417 to M.d.H.); the Swedish Heart-Lung Foundation (grants 20200781 and 20200602 to M.d.H.); the British Heart Foundation (to A.G.), the European Commission (grants LSHM-CT-2007-037273 and HEALTH-F2-2013-601456 to A.G.); the Novo Nordisk Foundation (grants NNF15CC0018486 to A.G. and NNF18CC0034900 to T.H.P.); the Lundbeck Foundation (grant R190-2014-3904 to T.H.P.); VIAgenomics (grant SP/19/2/344612 to A.G.); the Wellcome Trust (grants 090532/Z/09/Z, 203141/Z/16/Z to H.W., 104955/Z/14/Z to A. David, 090532 to M.I.M., 098381 to M.I.M., 106130 to M.I.M., 203141 to M.I.M., 212259 to M.I.M., 205915/Z/17/Z to I.P.); UKRI Innovation-HDR-UK Fellowship (grant MR/S003061/1 to R.J.S.); European Union’s Horizon 2020 research and innovation program LONGITOOLS (grant H2020-SC1-2019-874739 to M.A.K., A.U., Z.B. and I.P.); the European Foundation for the Study of Diabetes (to B.J. and M.A.K.); the Imperial Post-CCT Post-Doctoral Fellowship (to B.J.); the Academy of Medical Sciences (to B.J.); the National Institute for Health Research Imperial NIHR Biomedical Research Center (to B.J. and T.M.T.); the Engineering and Physical Sciences Research Council (to B.J.); the Society for Endocrinology (to B.J.); the British Society for Neuroendocrinology (to B.J.); Research England ‘Expanding excellence in England’ (to I.B.); the Research Foundation-Flanders (to V.L.); the Diabetes UK (to V. Salem, A.T.; BDA, 20/0006307 to I.P.); the Russian Science Foundation (grant 19-15-00115 to S.S.); the NIDDK (grant U01-DK105535 to M.I.M.); European Federation for the Study of Diabetes (to A.T.); the Agence Nationale de la Recherche (PreciDIAB, grant ANR-18-IBHU-0001 to J.G.M. and I.P.); the University of Lille mobility grant (to J.G.M.); the People-Centered Artificial Intelligence Institute, University of Surrey (Z.B., M.A.K., A. Demirkan and I.P.); the World Cancer Research Fund (to I.P.); the World Cancer Research Fund International (grant 2017/1641 to I.P.); the Royal Society (grant IEC\R2\181075 to I.P. and C.A.R.); the European Union through the ‘Fonds européen de développement regional’ (FEDER; to I.P.); the ‘Conseil Régional des Hauts-de-France’ (Hauts-de-France Regional Council; to I.P.); the ‘Métropole Européenne de Lille’ (MEL, European Metropolis of Lille; to I.P.).

    FundersFunder number
    Medical Research CouncilMR/L01341X/1, MR/R010676/1 , MR/R010676/1
    Public Health England
    UK Dementia Research Institute
    Alzheimer’s Research UK
    Alzheimer’s Society
    National Health and Medical Research Council552498, 339446, 619667, 1184726, 1150083, 1154434, 1155302
    Vetenskapsrådet2017-02688, 2020-02191, 2019-01417
    Swedish Heart-Lung Foundation 20200781 , 20200602
    British Heart Foundation
    European CommissionLSHM-CT-2007-037273 , HEALTH-F2-2013-601456
    Novo Nordisk FondenNNF15CC0018486, NNF18CC0034900
    The Lundbeck Foundation (LUCENS)R190-2014-3904
    VIAgenomicsSP/19/2/344612
    Wellcome Trust090532/Z/09/Z, 203141/Z/16/Z, 104955/Z/14/Z, 090532, 098381, 106130, 203141, 212259, 205915/Z/17/Z
    UK Research and InnovationMR/S003061/1
    Horizon EuropeH2020-SC1-2019-874739
    European Foundation for the Study of Diabetes
    Imperial College London
    Academy of Medical Sciences
    NIHR Biomedical Research Centre
    Engineering and Physical Sciences Research Council
    Society for Endocrinology
    British Society for Neuroendocrinology
    Research England
    Fonds Wetenschappelijk Onderzoek
    Diabetes UK20/0006307
    Russian Science Foundation19-15-00115
    National Institute of Diabetes and Digestive and Kidney DiseasesU01-DK105535
    European Foundation for the Study of Diabetes
    Agence Nationale de la ResearcheANR-18-IBHU-0001
    University of Lille
    University of Surrey
    World Cancer Research Fund 2017/1641
    The Royal SocietyIEC\R2\181075
    European Union
    Conseil Régional Hauts-de-France
    Métropole Européenne de Lille

    UN SDGs

    This output contributes to the following UN Sustainable Development Goals (SDGs)

    1. SDG 3 - Good Health and Well-being
      SDG 3 Good Health and Well-being

    Keywords

    • Blood Glucose
    • Colon
    • Diabetes Mellitus, Type 2
    • Genome-Wide Association Study
    • Glucose
    • Humans

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