Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification

Lagou, V.; Jiang, L.; Ulrich, A.; Zudina, L.; Gutierrez Gonzalez, K. S.; Balkhiyarova, Z.; Faggian, A.; Chen, S.; Todorov, P.; Sharapov, S.; David, A.; Marullo, L.; Mägi, R.; Rujan, R.-M.; Ahlqvist, E.; Thorleifsson, G.; Gao, H.; Evangelou, E.; Benyamin, B.; Scott, R.; Isaacs, A.; Zhao, J. H.; Willems, S. M.; Johnson, T.; Gieger, C.; Grallert, H.; Meisinger, C.; Müller-Nurasyid, M.; Strawbridge, R. J.; Goel, A.; Rybin, D.; Albrecht, E.; Jackson, A. U.; Stringham, H. M.; Correa, I. R.; Farber-Eber, E.; Steinthorsdottir, V.; Uitterlinden, A. G.; Munroe, P. B.; Brown, M. J.; Schmidberger, J.

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.