GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification
Authors: 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 ,   GWA-PA Consortium, 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 ,   Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC), van Duijn Cornelia M. 
Published: September 2023

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.