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; He Gao; ?vangelos ?vangelou; 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; 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; Marcel den Hoed; Aleksey Shmeliov; Marika Kaakinen; Benjamin Jones; Inga Prokopenko; Et al.; Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

doi:10.1038/s41588-023-01462-3

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, He Gao, ?vangelos ?vangelou, Beben BenyaminRobert 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, 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, Marcel den Hoed, Aleksey Shmeliov, Marika Kaakinen^*, Benjamin Jones^*, Inga Prokopenko^*, Et al., Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

^*Corresponding author for this work

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

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
Early online date	1 Sept 2023
DOIs	https://doi.org/10.1038/s41588-023-01462-3
Publication status	Published - Sept 2023

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Lagou, V., Jiang, L., Ulrich, A., Zudina, L., González, K. S. G., Balkhiyarova, Z., Faggian, A., Maina, J. G., Chen, S., Todorov, P. V., Sharapov, S., David, A., Marullo, L., Mägi, R., Rujan, R. M., Ahlqvist, E., Thorleifsson, G., Gao, H., ?vangelou, ., ... Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (2023). GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification. Nature Genetics, 55(9), 1448-1461. https://doi.org/10.1038/s41588-023-01462-3

@article{09378f282bb14c919b21f5d468a774af,

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 {\textquoteleft}around the clock{\textquoteright} 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.",

author = "Vasiliki Lagou and Longda Jiang and Anna Ulrich and Liudmila Zudina and Gonz{\'a}lez, {Karla Sofia Guti{\'e}rrez} and Zhanna Balkhiyarova and Alessia Faggian and Maina, {Jared G.} and Shiqian Chen and Todorov, {Petar V.} and Sodbo Sharapov and Alessia David and Letizia Marullo and Reedik M{\"a}gi and Rujan, {Roxana Maria} and Emma Ahlqvist and Gudmar Thorleifsson and He Gao and ?vangelos ?vangelou and Beben Benyamin and Scott, {Robert A.} and Aaron Isaacs and Zhao, {Jing Hua} and Willems, {Sara M.} and Toby Johnson and Christian Gieger and Harald Grallert and Christa Meisinger and Martina M{\"u}ller-Nurasyid and Strawbridge, {Rona J.} and Anuj Goel and Denis Rybin and Eva Albrecht and Jackson, {Anne U.} and Stringham, {Heather M.} and Corr{\^e}a, {Ivan R.} and Eric Farber-Eger and Valgerdur Steinthorsdottir and Uitterlinden, {Andr{\'e} G.} and Munroe, {Patricia B.} and Brown, {Morris J.} and Julian Schmidberger and Oddgeir Holmen and Barbara Thorand and Kristian Hveem and Tom Wilsgaard and Mohlke, {Karen L.} and Zhe Wang and {den Hoed}, Marcel and Aleksey Shmeliov and Marika Kaakinen and Benjamin Jones and Inga Prokopenko and {Et al.} and {Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)}",

note = "Funding Information: 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{\textquoteright}s Society (to P.E. and I.T.); the Alzheimer{\textquoteright}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{\textquoteright}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 {\textquoteleft}Expanding excellence in England{\textquoteright} (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 {\textquoteleft}Fonds europ{\'e}en de d{\'e}veloppement regional{\textquoteright} (FEDER; to I.P.); the {\textquoteleft}Conseil R{\'e}gional des Hauts-de-France{\textquoteright} (Hauts-de-France Regional Council; to I.P.); the {\textquoteleft}M{\'e}tropole Europ{\'e}enne de Lille{\textquoteright} (MEL, European Metropolis of Lille; to I.P.). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = sep,

doi = "10.1038/s41588-023-01462-3",

language = "English",

volume = "55",

pages = "1448--1461",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

Lagou, V, Jiang, L, Ulrich, A, Zudina, L, González, KSG, Balkhiyarova, Z, Faggian, A, Maina, JG, Chen, S, Todorov, PV, Sharapov, S, David, A, Marullo, L, Mägi, R, Rujan, RM, Ahlqvist, E, Thorleifsson, G, Gao, H, ?vangelou, Benyamin, B, Scott, RA, Isaacs, A, Zhao, JH, Willems, SM, Johnson, T, Gieger, C, Grallert, H, Meisinger, C, Müller-Nurasyid, M, Strawbridge, RJ, Goel, A, Rybin, D, Albrecht, E, Jackson, AU, Stringham, HM, Corrêa, IR, Farber-Eger, E, Steinthorsdottir, V, Uitterlinden, AG, Munroe, PB, Brown, MJ, Schmidberger, J, Holmen, O, Thorand, B, Hveem, K, Wilsgaard, T, Mohlke, KL, Wang, Z, den Hoed, M, Shmeliov, A, Kaakinen, M, Jones, B, Prokopenko, I, Et al. & Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) 2023, 'GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification', Nature Genetics, vol. 55, no. 9, pp. 1448-1461. https://doi.org/10.1038/s41588-023-01462-3

TY - JOUR

T1 - GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

AU - Lagou, Vasiliki

AU - Jiang, Longda

AU - Ulrich, Anna

AU - Zudina, Liudmila

AU - González, Karla Sofia Gutiérrez

AU - Balkhiyarova, Zhanna

AU - Faggian, Alessia

AU - Maina, Jared G.

AU - Chen, Shiqian

AU - Todorov, Petar V.

AU - Sharapov, Sodbo

AU - David, Alessia

AU - Marullo, Letizia

AU - Mägi, Reedik

AU - Rujan, Roxana Maria

AU - Ahlqvist, Emma

AU - Thorleifsson, Gudmar

AU - Gao, He

AU - ?vangelou, ?vangelos

AU - Benyamin, Beben

AU - Scott, Robert A.

AU - Isaacs, Aaron

AU - Zhao, Jing Hua

AU - Willems, Sara M.

AU - Johnson, Toby

AU - Gieger, Christian

AU - Grallert, Harald

AU - Meisinger, Christa

AU - Müller-Nurasyid, Martina

AU - Strawbridge, Rona J.

AU - Goel, Anuj

AU - Rybin, Denis

AU - Albrecht, Eva

AU - Jackson, Anne U.

AU - Stringham, Heather M.

AU - Corrêa, Ivan R.

AU - Farber-Eger, Eric

AU - Steinthorsdottir, Valgerdur

AU - Uitterlinden, André G.

AU - Munroe, Patricia B.

AU - Brown, Morris J.

AU - Schmidberger, Julian

AU - Holmen, Oddgeir

AU - Thorand, Barbara

AU - Hveem, Kristian

AU - Wilsgaard, Tom

AU - Mohlke, Karen L.

AU - Wang, Zhe

AU - den Hoed, Marcel

AU - Shmeliov, Aleksey

AU - Kaakinen, Marika

AU - Jones, Benjamin

AU - Prokopenko, Inga

AU - Et al.

AU - Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

N1 - Funding Information: 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.). Publisher Copyright: © 2023, The Author(s).

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

U2 - 10.1038/s41588-023-01462-3

DO - 10.1038/s41588-023-01462-3

M3 - Article

SN - 1061-4036

VL - 55

SP - 1448

EP - 1461

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -