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GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification. / Lagou, Vasiliki; Jiang, Longda; Ulrich, Anna; Zudina, Liudmila; González, Karla Sofia Gutiérrez; Balkhiyarova, Zhanna; Faggian, Alessia; Maina, Jared G.; Chen, Shiqian; Todorov, Petar V.; Sharapov, Sodbo; David, Alessia; Marullo, Letizia; Mägi, Reedik; Rujan, Roxana Maria; Ahlqvist, Emma; Thorleifsson, Gudmar; Gao, Ηe; Εvangelou, Εvangelos; Benyamin, Beben; Scott, Robert A.; Isaacs, Aaron; Zhao, Jing Hua; Willems, Sara M.; Johnson, Toby; Gieger, Christian; Grallert, Harald; Meisinger, Christa; Müller-Nurasyid, Martina; Strawbridge, Rona J.; Goel, Anuj; Rybin, Denis; Albrecht, Eva; Jackson, Anne U.; Stringham, Heather M.; Corrêa, Ivan R.; Farber-Eger, Eric; Steinthorsdottir, Valgerdur; Uitterlinden, André G.; Munroe, Patricia B.; Brown, Morris J.; Schmidberger, Julian; Holmen, Oddgeir; Thorand, Barbara; Hveem, Kristian; Wilsgaard, Tom; Mohlke, Karen L.; Wang, Zhe; den Hoed, Marcel; Shmeliov, Aleksey; den Hoed, Marcel; Loos, Ruth J.F.; Kratzer, Wolfgang; Haenle, Mark; Koenig, Wolfgang; Boehm, Bernhard O.; Tan, Tricia M.; Tomas, Alejandra; Salem, Victoria; Barroso, Inês; Tuomilehto, Jaakko; Boehnke, Michael; Florez, Jose C.; Hamsten, Anders; Watkins, Hugh; Njølstad, Inger; Wichmann, H. Erich; Caulfield, Mark J.; Khaw, Kay Tee; van Duijn, Cornelia M.; Hofman, Albert; Wareham, Nicholas J.; Langenberg, Claudia; Whitfield, John B.; Martin, Nicholas G.; Montgomery, Grant; Scapoli, Chiara; Tzoulaki, Ioanna; Elliott, Paul; Thorsteinsdottir, Unnur; Stefansson, Kari; Brittain, Evan L.; McCarthy, Mark I.; Froguel, Philippe; Sexton, Patrick M.; Wootten, Denise; Groop, Leif; Dupuis, Josée; Meigs, James B.; Deganutti, Giuseppe; Demirkan, Ayse; Pers, Tune H.; Reynolds, Christopher A.; Aulchenko, Yurii S.; Kaakinen, Marika A.; Jones, Ben; Prokopenko, Inga; van Duijn, Cornelia M.
In:
Nature Genetics, Vol. 55, No. 9, 2023, p. 1448-1461.
Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
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, Η, Εvangelou, Ε, 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, den Hoed, M
, Loos, RJF, Kratzer, W, Haenle, M, Koenig, W, Boehm, BO, Tan, TM, Tomas, A, Salem, V, Barroso, I, Tuomilehto, J, Boehnke, M, Florez, JC, Hamsten, A, Watkins, H, Njølstad, I, Wichmann, HE, Caulfield, MJ, Khaw, KT, van Duijn, CM, Hofman, A, Wareham, NJ, Langenberg, C, Whitfield, JB, Martin, NG, Montgomery, G, Scapoli, C, Tzoulaki, I, Elliott, P, Thorsteinsdottir, U, Stefansson, K, Brittain, EL, McCarthy, MI, Froguel, P, Sexton, PM, Wootten, D, Groop, L, Dupuis, J, Meigs, JB, Deganutti, G, Demirkan, A
, Pers, TH, Reynolds, CA, Aulchenko, YS, Kaakinen, MA, Jones, B, Prokopenko, I & van Duijn, CM 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/s41588-023-01462-3APA
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, Η., Εvangelou, Ε., ... van Duijn, C. M. (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/s41588-023-01462-3Vancouver
Lagou V, Jiang L, Ulrich A, Zudina L, González KSG, Balkhiyarova Z et al.
GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.
Nature Genetics. 2023;55(9):1448-1461.
https://doi.org/10.1038/s41588-023-01462-3Author
Lagou, Vasiliki ; Jiang, Longda ; Ulrich, Anna ; Zudina, Liudmila ; González, Karla Sofia Gutiérrez ; Balkhiyarova, Zhanna ; Faggian, Alessia ; Maina, Jared G. ; Chen, Shiqian ; Todorov, Petar V. ; Sharapov, Sodbo ; David, Alessia ; Marullo, Letizia ; Mägi, Reedik ; Rujan, Roxana Maria ; Ahlqvist, Emma ; Thorleifsson, Gudmar ; Gao, Ηe ; Εvangelou, Εvangelos ; Benyamin, Beben ; Scott, Robert A. ; Isaacs, Aaron ; Zhao, Jing Hua ; Willems, Sara M. ; Johnson, Toby ; Gieger, Christian ; Grallert, Harald ; Meisinger, Christa ; Müller-Nurasyid, Martina ; Strawbridge, Rona J. ; Goel, Anuj ; Rybin, Denis ; Albrecht, Eva ; Jackson, Anne U. ; Stringham, Heather M. ; Corrêa, Ivan R. ; Farber-Eger, Eric ; Steinthorsdottir, Valgerdur ; Uitterlinden, André G. ; Munroe, Patricia B. ; Brown, Morris J. ; Schmidberger, Julian ; Holmen, Oddgeir ; Thorand, Barbara ; Hveem, Kristian ; Wilsgaard, Tom ; Mohlke, Karen L. ; Wang, Zhe ; den Hoed, Marcel ; Shmeliov, Aleksey ; den Hoed, Marcel ; Loos, Ruth J.F. ; Kratzer, Wolfgang ; Haenle, Mark ; Koenig, Wolfgang ; Boehm, Bernhard O. ; Tan, Tricia M. ; Tomas, Alejandra ; Salem, Victoria ; Barroso, Inês ; Tuomilehto, Jaakko ; Boehnke, Michael ; Florez, Jose C. ; Hamsten, Anders ; Watkins, Hugh ; Njølstad, Inger ; Wichmann, H. Erich ; Caulfield, Mark J. ; Khaw, Kay Tee ; van Duijn, Cornelia M. ; Hofman, Albert ; Wareham, Nicholas J. ; Langenberg, Claudia ; Whitfield, John B. ; Martin, Nicholas G. ; Montgomery, Grant ; Scapoli, Chiara ; Tzoulaki, Ioanna ; Elliott, Paul ; Thorsteinsdottir, Unnur ; Stefansson, Kari ; Brittain, Evan L. ; McCarthy, Mark I. ; Froguel, Philippe ; Sexton, Patrick M. ; Wootten, Denise ; Groop, Leif ; Dupuis, Josée ; Meigs, James B. ; Deganutti, Giuseppe ; Demirkan, Ayse ; Pers, Tune H. ; Reynolds, Christopher A. ; Aulchenko, Yurii S. ; Kaakinen, Marika A. ; Jones, Ben ; Prokopenko, Inga ; van Duijn, Cornelia M. / GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification. In: Nature Genetics. 2023 ; Vol. 55, No. 9. pp. 1448-1461.
Bibtex
@article{b485fae05d4a458187f3ccce684cad62,
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 Ηe Gao and Εvangelos Εvangelou 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 {den Hoed}, Marcel and Loos, {Ruth J.F.} and Wolfgang Kratzer and Mark Haenle and Wolfgang Koenig and Boehm, {Bernhard O.} and Tan, {Tricia M.} and Alejandra Tomas and Victoria Salem and In{\^e}s Barroso and Jaakko Tuomilehto and Michael Boehnke and Florez, {Jose C.} and Anders Hamsten and Hugh Watkins and Inger Nj{\o}lstad and Wichmann, {H. Erich} and Caulfield, {Mark J.} and Khaw, {Kay Tee} and {van Duijn}, {Cornelia M.} and Albert Hofman and Wareham, {Nicholas J.} and Claudia Langenberg and Whitfield, {John B.} and Martin, {Nicholas G.} and Grant Montgomery and Chiara Scapoli and Ioanna Tzoulaki and Paul Elliott and Unnur Thorsteinsdottir and Kari Stefansson and Brittain, {Evan L.} and McCarthy, {Mark I.} and Philippe Froguel and Sexton, {Patrick M.} and Denise Wootten and Leif Groop and Jos{\'e}e Dupuis and Meigs, {James B.} and Giuseppe Deganutti and Ayse Demirkan and Pers, {Tune H.} and Reynolds, {Christopher A.} and Aulchenko, {Yurii S.} and Kaakinen, {Marika A.} and Ben Jones and Inga Prokopenko and {van Duijn}, {Cornelia M.}",
note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
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",
}
RIS
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, Ηe
AU - Εvangelou, Εvangelos
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 - den Hoed, Marcel
AU - Loos, Ruth J.F.
AU - Kratzer, Wolfgang
AU - Haenle, Mark
AU - Koenig, Wolfgang
AU - Boehm, Bernhard O.
AU - Tan, Tricia M.
AU - Tomas, Alejandra
AU - Salem, Victoria
AU - Barroso, Inês
AU - Tuomilehto, Jaakko
AU - Boehnke, Michael
AU - Florez, Jose C.
AU - Hamsten, Anders
AU - Watkins, Hugh
AU - Njølstad, Inger
AU - Wichmann, H. Erich
AU - Caulfield, Mark J.
AU - Khaw, Kay Tee
AU - van Duijn, Cornelia M.
AU - Hofman, Albert
AU - Wareham, Nicholas J.
AU - Langenberg, Claudia
AU - Whitfield, John B.
AU - Martin, Nicholas G.
AU - Montgomery, Grant
AU - Scapoli, Chiara
AU - Tzoulaki, Ioanna
AU - Elliott, Paul
AU - Thorsteinsdottir, Unnur
AU - Stefansson, Kari
AU - Brittain, Evan L.
AU - McCarthy, Mark I.
AU - Froguel, Philippe
AU - Sexton, Patrick M.
AU - Wootten, Denise
AU - Groop, Leif
AU - Dupuis, Josée
AU - Meigs, James B.
AU - Deganutti, Giuseppe
AU - Demirkan, Ayse
AU - Pers, Tune H.
AU - Reynolds, Christopher A.
AU - Aulchenko, Yurii S.
AU - Kaakinen, Marika A.
AU - Jones, Ben
AU - Prokopenko, Inga
AU - van Duijn, Cornelia M.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023
Y1 - 2023
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 - Journal article
C2 - 37679419
AN - SCOPUS:85170159626
VL - 55
SP - 1448
EP - 1461
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 9
ER -
