TY - UNPB
T1 - Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification
AU - Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)
AU - Deganutti, Giuseppe
AU - Lagou, Vasiliki
AU - Jiang, Longda
AU - Ulrich, Anna
AU - Zudina, Liudmila
AU - González, Karla Sofia Gutiérrez
AU - Balkhiyarova, Zhanna
AU - Faggian, Alessia
AU - Chen, Shiqian
AU - Todorov, Petar
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 - Evangelou, Evangelos K.
AU - Benyamin, Beben
AU - Scott, Robert
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 Jr, Ivan R
AU - Eric, Farber-Eber
AU - Steinthorsdottir, Valgerdur
AU - Uitterlinden, André G
AU - Munroe, Patricia B
AU - Brown, Morris J
AU - Julian, Schmidberger
AU - Holmen, Oddgeir
AU - Thorand, Barbara
AU - Hveem, Kristian
AU - Wilsgaard, Tom
AU - Mohlke, Karen L
AU - Kratzer, Wolfgang
AU - Mark, Haenle
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 L
AU - Groop, Leif
AU - Dupuis, Josée
AU - Meigs, James B
AU - Deganutti, Giuseppe
AU - Demirkan, Ayse
AU - Pers, Tune H
AU - Reynolds, Chris
AU - Aulchenko, Yurii S
AU - Kaakinen, Marika A
AU - Jones, Ben J.
AU - Prokopenko, Inga
PY - 2023
Y1 - 2023
N2 - Homeostatic control of blood glucose requires different physiological responses in the fasting and post-prandial states. We reasoned that glucose measurements under non-standardised conditions (random glucose; RG) may capture diverse glucoregulatory processes more effectively than previous genome-wide association studies (GWAS) of fasting glycaemia or after standardised glucose loads. Through GWAS meta-analysis of RG in 493,036 individuals without diabetes of diverse ethnicities we identified 128 associated loci represented by 162 distinct signals, including 14 with sex-dimorphic effects, 9 discovered through trans-ethnic analysis, and 70 novel signals for glycaemic traits. Novel RG loci were particularly enriched in expression in the ileum and colon, indicating a prominent role for the gastrointestinal tract in the control of blood glucose. Functional studies and molecular dynamics simulations of coding variants of GLP1R, a well-established type 2 diabetes treatment target, provided a genetic framework for optimal selection of GLP-1R agonist therapy. We also provided new evidence from Mendelian randomisation that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Thus, our approach based on RG GWAS provided wide-ranging insights into the biology of glucose regulation, diabetes complications and the potential for treatment
AB - Homeostatic control of blood glucose requires different physiological responses in the fasting and post-prandial states. We reasoned that glucose measurements under non-standardised conditions (random glucose; RG) may capture diverse glucoregulatory processes more effectively than previous genome-wide association studies (GWAS) of fasting glycaemia or after standardised glucose loads. Through GWAS meta-analysis of RG in 493,036 individuals without diabetes of diverse ethnicities we identified 128 associated loci represented by 162 distinct signals, including 14 with sex-dimorphic effects, 9 discovered through trans-ethnic analysis, and 70 novel signals for glycaemic traits. Novel RG loci were particularly enriched in expression in the ileum and colon, indicating a prominent role for the gastrointestinal tract in the control of blood glucose. Functional studies and molecular dynamics simulations of coding variants of GLP1R, a well-established type 2 diabetes treatment target, provided a genetic framework for optimal selection of GLP-1R agonist therapy. We also provided new evidence from Mendelian randomisation that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Thus, our approach based on RG GWAS provided wide-ranging insights into the biology of glucose regulation, diabetes complications and the potential for treatment
U2 - 10.1101/2021.04.17.21255471
DO - 10.1101/2021.04.17.21255471
M3 - Preprint
T3 - Nature Genetics
BT - Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification
ER -
SDG 3 Good Health and Well-being