Open Access

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, Ηe Gao, Εvangelos Εvangelou, 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, 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 Njølstad, H.-Erich Wichmann, Mark J. Caulfield, Kay-Tee Khaw, Cornelia M. 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, Mark I. McCarthy, Philippe Froguel, Patrick M. Sexton, Denise Wootten, Leif Groop, Josée Dupuis, James B. Meigs, Giuseppe Deganutti, Ayse Demirkan, Tune H. Pers, Christopher A. Reynolds, Yurii S. Aulchenko, Marika A. Kaakinen, Ben Jones, Inga Prokopenko

• 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 receptorConventional 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.…