학술논문
GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification
Document Type
Original Paper
Author
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, Jr., 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; 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
Source
Nature Genetics. 55(9):1448-1461
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
Abstract
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.
Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.