GLP1R expression protects against 58 diseases but raises risk for 34 diseases and neonatal health

Abstract

Cardiometabolic gene-target drugs such as Glucagon-Like Peptide 1 Receptor agonists are used extensively, yet risks and repurposing have not been systematically evaluated across a comprehensive set of diseases. We use Phenome-wide Mendelian Randomization to test GLP1R gene expression and Cholesteryl Ester Transfer Protein (CETP) concentration, two promising cardiometabolic drug targets, on risk of 396 diseases based on sex-specific, ancestry-specific, genome-wide association studies in UK Biobank. We identify 92 causal effects (66 novel) of genetically proxied GLP1R expression on disease, with 58 protective and 34 risk effects. Risks of GLP1R expression on neonatal health raise concern for women who may become pregnant. GLP1R expression substantially increases risk of Vitamin D deficiency. Although GLP1R is hypothesized as anti-ageing, we find it increases risk of 22 age-related diseases. Conversely, we find CETP inhibition is narrowly cardioprotective. Results show benefits, risks and repurposing opportunities for GLP1R-targetted and CETP-targeted drugs.