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 language | English |
|---|---|
| Pages (from-to) | 1448-1461 |
| Number of pages | 14 |
| Journal | Nature Genetics |
| Volume | 55 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 7 Sept 2023 |
Bibliographical note
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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.).
| Funders | Funder number |
|---|---|
| Medical Research Council | MR/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 Council | 552498, 339446, 619667, 1184726, 1150083, 1154434, 1155302 |
| Vetenskapsrådet | 2017-02688, 2020-02191, 2019-01417 |
| Swedish Heart-Lung Foundation | 20200781 , 20200602 |
| British Heart Foundation | |
| European Commission | LSHM-CT-2007-037273 , HEALTH-F2-2013-601456 |
| Novo Nordisk Fonden | NNF15CC0018486, NNF18CC0034900 |
| The Lundbeck Foundation (LUCENS) | R190-2014-3904 |
| VIAgenomics | SP/19/2/344612 |
| Wellcome Trust | 090532/Z/09/Z, 203141/Z/16/Z, 104955/Z/14/Z, 090532, 098381, 106130, 203141, 212259, 205915/Z/17/Z |
| UK Research and Innovation | MR/S003061/1 |
| Horizon Europe | H2020-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 UK | 20/0006307 |
| Russian Science Foundation | 19-15-00115 |
| National Institute of Diabetes and Digestive and Kidney Diseases | U01-DK105535 |
| European Foundation for the Study of Diabetes | |
| Agence Nationale de la Researche | ANR-18-IBHU-0001 |
| University of Lille | |
| University of Surrey | |
| World Cancer Research Fund | 2017/1641 |
| The Royal Society | IEC\R2\181075 |
| European Union | |
| Conseil Régional Hauts-de-France | |
| Métropole Européenne de Lille |
Keywords
- Blood Glucose
- Colon
- Diabetes Mellitus, Type 2
- Genome-Wide Association Study
- Glucose
- Humans
