Random glucose GWAS in 493,036 individuals provides 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 , Chen Shiqian , Todorov Petar , Sharapov Sodbo , David Alessia , Marullo Letizia , Mägi Reedik , Rujan Roxana-Maria , Ahlqvist Emma , Thorleifsson Gudmar , Gao He , Evangelou Evangelos , Benyamin Beben , Scott Robert , 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 , Eric Farber-Eber , Steinthorsdottir Valgerdur , Uitterlinden André G , Munroe Patricia B , Brown Morris J , Julian Schmidberger , Holmen Oddgeir , Thorand Barbara , Hveem Kristian , Wilsgaard Tom , Mohlke Karen L , Kratzer Wolfgang , Mark Haenle , 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 , 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 
Published: April 2021

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.