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

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 (+80 others)
2021 medRxiv   pre-print

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https://web.archive.org/web/20210717091531/https://www.medrxiv.org/content/medrxiv/early/2021/04/20/2021.04.17.21255471.full.pdf

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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
more » ... 8 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.
doi:10.1101/2021.04.17.21255471 fatcat:gxubyihat5ehpcholgrwc2beye
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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, 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 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, 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). "Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification." medRxiv (2021)