GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.
Lagou V., Jiang L., Ulrich A., Zudina L., González KSG., Balkhiyarova Z., Faggian A., Maina JG., Chen S., Todorov PV., Sharapov S., David A., Marullo L., Mägi R., Rujan R-M., Ahlqvist E., Thorleifsson G., Gao Η., Εvangelou Ε., Benyamin B., Scott RA., Isaacs A., Zhao JH., Willems SM., Johnson T., Gieger C., Grallert H., Meisinger C., Müller-Nurasyid M., Strawbridge RJ., Goel A., Rybin D., Albrecht E., Jackson AU., Stringham HM., Corrêa IR., Farber-Eger E., Steinthorsdottir V., Uitterlinden AG., Munroe PB., Brown MJ., Schmidberger J., Holmen O., Thorand B., Hveem K., Wilsgaard T., Mohlke KL., Wang Z., GWA-PA Consortium None., Shmeliov A., den Hoed M., Loos RJF., Kratzer W., Haenle M., Koenig W., Boehm BO., Tan TM., Tomas A., Salem V., Barroso I., Tuomilehto J., Boehnke M., Florez JC., Hamsten A., Watkins H., Njølstad I., Wichmann H-E., Caulfield MJ., Khaw K-T., van Duijn CM., Hofman A., Wareham NJ., Langenberg C., Whitfield JB., Martin NG., Montgomery G., Scapoli C., Tzoulaki I., Elliott P., Thorsteinsdottir U., Stefansson K., Brittain EL., McCarthy MI., Froguel P., Sexton PM., Wootten D., Groop L., Dupuis J., Meigs JB., Deganutti G., Demirkan A., Pers TH., Reynolds CA., Aulchenko YS., Kaakinen MA., Jones B., Prokopenko I., Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC) None.
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.