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Nature Genetics

Publication date: 2023-09-01
Volume: 55 Pages: 1448 -
Publisher: Nature Research

Author:

Lagou, Vasiliki
Jiang, Longda ; Ulrich, Anna ; Zudina, Liudmila ; Gonzalez, Karla Sofia Gutierrez ; Balkhiyarova, Zhanna ; Faggian, Alessia ; Maina, Jared G ; Chen, Shiqian ; Todorov, Petar V ; Sharapov, Sodbo ; David, Alessia ; Marullo, Letizia ; Magi, Reedik ; Rujan, Roxana-Maria ; Ahlqvist, Emma ; Thorleifsson, Gudmar ; Gao, He ; Evangelou, Evangelos ; Benyamin, Beben ; Scott, Robert A ; Isaacs, Aaron ; Zhao, Jing Hua ; Willems, Sara M ; Johnson, Toby ; Gieger, Christian ; Grallert, Harald ; Meisinger, Christa ; Mueller-Nurasyid, Martina ; Strawbridge, Rona J ; Goel, Anuj ; Rybin, Denis ; Albrecht, Eva ; Jackson, Anne U ; Stringham, Heather M ; Correa, Ivan R ; Farber-Eger, Eric ; Steinthorsdottir, Valgerdur ; Uitterlinden, Andre 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 JF ; Kratzer, Wolfgang ; Haenle, Mark ; Koenig, Wolfgang ; Boehm, Bernhard O ; Tan, Tricia M ; Tomas, Alejandra ; Salem, Victoria ; Barroso, Ines ; Tuomilehto, Jaakko ; Boehnke, Michael ; Florez, Jose C ; Hamsten, Anders ; Watkins, Hugh ; Njolstad, 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, Josee ; Meigs, James B ; Deganutti, Giuseppe ; Demirkan, Ayse ; Pers, Tune H ; Reynolds, Christopher A ; Aulchenko, Yurii S ; Kaakinen, Marika A ; Jones, Ben ; Prokopenko, Inga

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, GENOME-WIDE ASSOCIATION, GENETIC-LOCI, CARDIOMETABOLIC RISK, ANALYSES IDENTIFY, TYPE-2, RECEPTOR, HERITABILITY, SCALE, METAANALYSIS, ANNOTATION, Humans, Glucose, Genome-Wide Association Study, Blood Glucose, Diabetes Mellitus, Type 2, Colon, GWA-PA Consortium, Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC), 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics

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.