GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

GWA-PA Consortium, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), Aleksey Shmeliov, Marcel den Hoed, Ruth J. F. Loos, 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 M 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 L Wootten, Leif Groop, Josée Dupuis, James B Meigs, Giuseppe Deganutti, Ayse Demirkan, Tune H Pers, Chris Reynolds, Yurii S Aulchenko, Marika A Kaakinen, Ben J. Jones, Inga Prokopenko

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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.

Original languageEnglish
Pages (from-to)1448-1461
Number of pages14
JournalNature Genetics
Volume55
Issue number9
DOIs
Publication statusPublished - 7 Sept 2023

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Keywords

  • Blood Glucose
  • Colon
  • Diabetes Mellitus, Type 2
  • Genome-Wide Association Study
  • Glucose
  • Humans

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