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Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification

By Vasiliki Lagou, Longda Jiang, Anna Ulrich, Liudmila Zudina, Karla Sofia Gutiérrez González, Zhanna Balkhiyarova, Alessia Faggian, Shiqian Chen, Petar Todorov, Sodbo Sharapov, Alessia David, Letizia Marullo, Reedik Mägi, Roxana-Maria Rujan, Emma Ahlqvist, Gudmar Thorleifsson, He Gao, Evangelos Evangelou, Beben Benyamin, Robert 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-Eber, Valgerdur Steinthorsdottir, André G. Uitterlinden, Patricia B Munroe, Morris J. Brown, Julian Schmidberger, Oddgeir Holmen, Barbara Thorand, Kristian Hveem, Tom Wilsgaard, Karen L. Mohlke, Wolfgang Kratzer, Haenle Mark, Wolfgang Koenig, Bernhard O Boehm, Tricia M Tan, Alejandra Tomas, Victoria Salem, Ines Barroso, Jaakko Tuomilehto, Michael Boehnke, Jose C Florez, Anders Hamsten, Hugh Watkins, Inger Njølstad, H.-Erich Wichmann, Mark J. Caulfield, Kay-Tee Khaw, Cornelia 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 McCarthy, Philippe Froguel, Patrick M. Sexton, Denise Wootten, Leif Groop, Josee Dupuis, James B Meigs, Giuseppe Deganutti, Ayse Demirkan, Tune H Pers, Christopher A Reynolds, Yurii S Aulchenko, Marika A. Kaakinen, Ben Jones, Inga Prokopenko, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)

Posted 20 Apr 2021
medRxiv DOI: 10.1101/2021.04.17.21255471

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 stratification.

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