Genetic architecture of incretin and glucagon regulation revealed by genome and exome-wide analysis in the Fenland cohort

Abstract The receptors for glucagon and incretin hormones: glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), are key therapeutic targets for Type 2 diabetes (T2D) and obesity treatments. To better understand the metabolic hormones biology, we performed genome-wide association study (GWAS), and exome-based rare-variant analysis for immunoassay-measured GIP, GLP-1 and glucagon at fasting (T0) and 120-minutes post-oral glucose load (T120) in the Fenland Study. We identified 16 GWAS associations including 5 at T0 including at PDE3B with glucagon T0 , and 10 at T120 including at SLC38A4 with glucagon T120 , highlighting the value of hormone measures post-glucose load. We demonstrated high expression of Slc38a4 in mouse α-cells, and SLC38A4 amino acid substrates triggered calcium influx and glucagon secretion. Secondary analysis of hormonal change (T120-T0) highlights ANO1 with GIP (T120−T0) . We also showed that cAMP-stimulated GIP secretion was abolished in ANO1 knockout duodenal organoids. Rare-variant analysis identified 6 associations, including GCGR. Links between PDE3B with glucagon and central adiposity emerged across both common and rare-variant analyses. These findings implicate biologically actionable pathways and provide a genetic foundation for mechanistic investigations and optimising metabolic disease therapeutics.