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; Ayse Demirkan; Karla Sofia Gutiérrez González; Marika Kaakinen; Inga Prokopenko; Zhanna Balkhiiarova; Alessia Faggian; Jared G. Maina; Shiqian Chen; Petar V. Todorov; Sodbo Sharapov; Alessia David; Letizia Marullo; Reedik Magi; Gudmar Thorleifsson; He Gao; Roxana-Maria Rujan; Emma Ahlqvist; Evangelos Evangelou; Beben Benyamin; Robert A Scott; Aaron Isaacs; Jing Hua Zhao; Sara M. Willems; Toby Johnson; Christian Gieger; Harald Grallert; Christa Meisinger; Martina Mueller-Nurasyid; Rona J Strawbridge; Anuj Goel; Denis Rybin; Eva Albrecht; Anne U Jackson; Heather M Stringham; Ivan R., Jr Correa; Eric Farber-Eger; Valgerdur Steinthorsdottir; Andre G. Uitterlinden; Patricia B. Munroe; Morris J. Brown; Julian Schmidberger; Oddgeir Holmen; Barbara Thorand; Kristian Hveem; Tom Wilsgaard; Karen L Mohlke; Zhe Wang; Aleksey Shmeliov; Marcel den Hoed; Ruth J F Loos; Wolfgang Kratzer; Mark Haenle; 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 Njolstad; H-Erich Wichmann; Mark J Caulfield; Kay-Tee Khaw; Cornelia 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; MI McCarthy; Philippe Froguel; Patrick M. Sexton; Denise Wootten; Leif Groop; Josée Dupuis; James B Meigs; Giuseppe Deganutti; Tune H. Pers; Christopher A. Reynolds; Yurii S. Aulchenko; Ben Jones

doi:10.1038/s41588-023-01462-3

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

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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, Ayse Demirkan, Karla Sofia Gutiérrez González, Marika Kaakinen, Inga Prokopenko, Zhanna Balkhiiarova, Alessia Faggian, …

Nature Genetics, Vol.55(9), pp.1448-1461

07/09/2023

DOI: https://doi.org/10.1038/s41588-023-01462-3

PMID: 37679419

Abstract

Basic Medicine

Endocrinology and Diabetes

Endokrinologi och diabetes

Klinisk medicin

Medical and Health Sciences

Medicin och hälsovetenskap

Medicinsk genetik

Medicinska och farmaceutiska grundvetenskaper

Clinical Medicine

Medical Genetics

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. Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

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Title: GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification
Creators: Vasiliki Lagou (Author)
Longda Jiang
Anna Ulrich (Author) - University of Surrey, School of Biosciences
Liudmila Zudina (Author) - University of Surrey, School of Biosciences
Ayse Demirkan (Author) - University of Surrey, School of Biosciences
Karla Sofia Gutiérrez González
Marika Kaakinen (Corresponding Author) - University of Surrey, School of Biosciences
Inga Prokopenko (Corresponding Author) - University of Surrey, School of Biosciences
Zhanna Balkhiiarova (Author) - University of Surrey, School of Biosciences
Alessia Faggian
Jared G. Maina
Shiqian Chen - Imperial Coll London, Sect Endocrinol & Invest Med, London, England
Petar V. Todorov - Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark
Sodbo Sharapov
Alessia David - Imperial Coll London, Dept Life Sci, Ctr Bioinformat & Syst Biol, London, England
Letizia Marullo - Univ Ferrara, Genet Sect, Dept Evolutionary Biol, Ferrara, Italy
Reedik Magi - Univ Tartu, Inst Genom, Estonian Genome Ctr, Tartu, Estonia
Gudmar Thorleifsson - Amgen Inc, deCODE Genet, Reykjavik, Iceland
He Gao - Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England
Roxana-Maria Rujan - Coventry Univ, Ctr Sports Exercise & Life Sci, Coventry, W Midlands, England
Emma Ahlqvist - Lund Univ, Ctr Diabet, Dept Clin Sci Malmö, Malmö, Sweden
Evangelos Evangelou
Beben Benyamin
Robert A Scott - Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England
Aaron Isaacs
Jing Hua Zhao - Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England
Sara M. Willems - Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Toby Johnson - Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Clin Pharmacol, London, England
Christian Gieger
Harald Grallert
Christa Meisinger - Univ Augsburg, Epidemiol, Fac Med, Augsburg, Germany
Martina Mueller-Nurasyid
Rona J Strawbridge
Anuj Goel
Denis Rybin - Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
Eva Albrecht - German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany
Anne U Jackson
Heather M Stringham
Ivan R., Jr Correa - New England Biolabs Inc, Ipswich, MA USA
Eric Farber-Eger
Valgerdur Steinthorsdottir - Amgen Inc, deCODE Genet, Reykjavik, Iceland
Andre G. Uitterlinden
Patricia B. Munroe
Morris J. Brown - Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Clin Pharmacol, London, England
Julian Schmidberger - Ulm Univ, Dept Internal Med 1, Med Ctr, Ulm, Germany
Oddgeir Holmen - Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Trondheim, Norway
Barbara Thorand
Kristian Hveem - Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, KG Jebsen Ctr Genet Epdiemiol, Trondheim, Norway
Tom Wilsgaard
Karen L Mohlke - Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA
Zhe Wang - Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA
Aleksey Shmeliov - Univ Surrey, Sch Biosci & Med, Dept Clin & Expt Med, Guildford, Surrey, England
Marcel den Hoed
Ruth J F Loos
Wolfgang Kratzer - Ulm Univ, Dept Internal Med 1, Med Ctr, Ulm, Germany
Mark Haenle - Ulm Univ, Dept Internal Med 1, Med Ctr, Ulm, Germany
Wolfgang Koenig
Bernhard O. Boehm
Tricia M. Tan - Imperial Coll London, Sect Endocrinol & Invest Med, London, England
Alejandra Tomas - Imperial Coll London, Sect Cell Biol & Funct Genom, London, England
Victoria Salem - Imperial Coll London, Dept Bioengn, South Kensington Campus, London, England
Inês Barroso - Univ Exeter, Sch Med, Exeter Ctr Excellence Diabet Res EXCEED, Exeter, Devon, England
Jaakko Tuomilehto
Michael Boehnke
Jose C. Florez
Anders Hamsten
Hugh Watkins
Inger Njolstad
H-Erich Wichmann - German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany
Mark J Caulfield
Kay-Tee Khaw - Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England
Cornelia van Duijn
Albert Hofman
Nicholas J. Wareham - Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England
Claudia Langenberg
John B. Whitfield - QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia
Nicholas G. Martin - QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia
Grant Montgomery
Chiara Scapoli - Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy
Ioanna Tzoulaki
Paul Elliott
Unnur Thorsteinsdottir
Kari Stefansson
Evan L. Brittain
MI McCarthy
Philippe Froguel
Patrick M. Sexton
Denise Wootten
Leif Groop
Josée Dupuis
James B Meigs
Giuseppe Deganutti - Coventry Univ, Ctr Sports Exercise & Life Sci, Coventry, W Midlands, England
Tune H. Pers - Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark
Christopher A. Reynolds
Yurii S. Aulchenko
Ben Jones - Imperial Coll London, Sect Endocrinol & Invest Med, London, England
Publication Details: Nature Genetics, Vol.55(9), pp.1448-1461
Publisher: Nature Research
Date published: 07/09/2023
Date accepted: 27/06/2023
Grants: Engineering and Physical Sciences Research Council (United Kingdom, Swindon) - EPSRC
University of Surrey (United Kingdom, Guildford)
Research England (United Kingdom, Bristol)
IEC\R2\181075, Royal Society of Medicine (United Kingdom, London) - RSM
2017/1641, World Cancer Research Fund International (United Kingdom, London)
British Heart Foundation (United Kingdom, London) - BHF
European Union (Belgium, Brussels) - EU
NIHR Imperial Biomedical Research Centre (United Kingdom, London) - BRC
Research Foundation - Flanders (Belgium, Brussels) - FWO
Diabetes UK (United Kingdom, London)
20/0006307, Diabetes UK (United Kingdom, London)
Longitools, H2020-SCI-2019-874739, Horizon 2020
MR/R010676/1, Medical Research Council (United Kingdom, London) - MRC
MR/L01341X/1, Medical Research Council (United Kingdom, London) - MRC
Fellowship Scheme, 552498, National Health and Medical Research Council (Australia, Canberra) - NHMRC
Fellowship Scheme, 339446, National Health and Medical Research Council (Australia, Canberra) - NHMRC
Fellowship Scheme, 619667, National Health and Medical Research Council (Australia, Canberra) - NHMRC
1184726, National Health and Medical Research Council (Australia, Canberra) - NHMRC
1150083, National Health and Medical Research Council (Australia, Canberra) - NHMRC
1154434, National Health and Medical Research Council (Australia, Canberra) - NHMRC
1155302, National Health and Medical Research Council (Australia, Canberra) - NHMRC
2017-02688, Swedish Research Council (Sweden, Stockholm) - VR
2020-02191, Swedish Research Council (Sweden, Stockholm) - VR
2019-01417, Swedish Research Council (Sweden, Stockholm) - VR
20200781, Swedish Heart-Lung Foundation (Sweden, Stockholm)
20200602, Swedish Heart-Lung Foundation (Sweden, Stockholm)
LSHM-CT-2007-037273, European Commission (Belgium, Brussels) - EC
HEALTH-F2-2013-601456, European Commission (Belgium, Brussels) - EC
NNF15CC0018486, Novo Nordisk Foundation (Denmark, Copenhagen) - NNF
NNF18CC0034900 , Novo Nordisk Foundation (Denmark, Copenhagen) - NNF
R190-2014-3904, Lundbeck Foundation (Denmark, Copenhagen)
090532/Z/09/Z, Wellcome Trust (United Kingdom, London) - WT
203141/Z/16/Z, Wellcome Trust (United Kingdom, London) - WT
104955/Z/14/Z, Wellcome Trust (United Kingdom, London) - WT
090532, Wellcome Trust (United Kingdom, London) - WT
098381, Wellcome Trust (United Kingdom, London) - WT
106130, Wellcome Trust (United Kingdom, London) - WT
203141, Wellcome Trust (United Kingdom, London) - WT
212259, Wellcome Trust (United Kingdom, London) - WT
205915/Z/17/Z, Wellcome Trust (United Kingdom, London) - WT
Innovation-HDR-UK Fellowship, MR/S003061/1, UK Research and Innovation (United Kingdom, Swindon) - UKRI
LONGITOOLS, H2020-SC1-2019-874739, European Union (Belgium, Brussels) - EU
European Foundation for the Study of Diabetes (Germany, Dusseldorf) - EFSD
Society for Endocrinology (United Kingdom, Bristol)
19-15-00115, Russian Science Foundation (Russia, Moscow)
U01-DK105535 , National Institute of Diabetes and Digestive and Kidney Diseases (United States, Bethesda) - NIDDK
Université de Lille (France, Lille) - UDL
World Cancer Research Fund UK (United Kingdom, London) - WCRF UK
Conseil Régional des Hauts-de-France (France, Lille)
Grant note: This research has been conducted using the UK Biobank Resource, project number 37685. 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.).
Identifiers: 99836265102346
Academic Unit: Institute for Sustainability; School of Biosciences
Language: English
Resource Type: Journal article
SDG (Scopus 2023): SDG 3

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

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