0224 The implication of the understudied druggable orphan GPCRs in sleep and cardiometabolic traits

Abstract

Abstract Introduction G-protein coupled receptors (GPCRs) are the largest class of membrane receptors. They are involved in various sleep and cardiometabolic disorders; however, 150 out of 900 GPCRs remain orphans (oGPCRs) with unknown endogenous ligands; thereby, limiting our understanding of their biological function. GPCRs are targeted by 36 % of FDA-approved drugs; thus, the understudied oGPCRs are druggable and have a high potential to impact human health once disease associations are made. Methods This study aimed to use a genomic approach from a large dataset to deorphanize oGPCRs whose genetic variations significantly impact sleep and cardiometabolic disorders. First, we used the UK Biobank study summary statistics to identify oGPCRs loci where multiple sleep and cardiometabolic traits colocalized at a false discovery rate < 5%. Next, in the metabolic disease knowledge portal, we performed PheWAS analysis of the variants to identify new phenotypic traits in other datasets of European ancestry. We then used GTex to identify quantitative trait loci to highlight variants that affect gene expression. Results Our study identified variants in oGPCRs GPR61, GPR146, and GPRC5B that have a pleiotropic effect in sleep and cardiometabolic traits in the UK Biobank cohort. The variant rs12044778 is an intronic variant in GPR61 associated with ease of waking up and morningness chronotype. GPR146's intronic variant rs1997243 showed an association with cholesterol level (HDL and LDL) and blood pressure; additionally, rs1997243 significantly increased the expression of GPR146 in adipose tissues. Finally, the intronic variant rs11639988 is associated with a decrease in BMI, and that it significantly decreased GPRC5B gene expression in the nucleus accumbens and adipose tissues. Conclusion Overall, our study provides new insight into the functions of oGPCRs genetic variants in sleep and cardiometabolic processes. Support (If Any) 5T32HL007609-35