Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank

Abstract

G protein-coupled receptors (GPCRs) drive an array of important physiological functions and are the targets of nearly one-third of all FDA approved drugs. Large scale genomic initiatives are mapping the genetic diversity in GPCRs, however, a map of which GPCR genetic variants are associated with phenotypic variation and disease is lacking. Furthermore, the mechanistic basis of how the individual GPCR genetic variants regulate molecular function is also largely unknown. We performed a phenome-wide association analysis for 269 common protein-altering variants in 156 GPCRs and 275 phenotypes using data from 337,205 unrelated white British UK Biobank participants and identified 138 associations at a false discovery rate of 5%. We found a novel association between rs12295710 in MRGPRE, a member of the Mas-related receptor family involved in nociception, and migraine risk. We also identified an association between rs3732378, a missense mutation in the binding pocket of CX3CR1, and hypothyroidism. Five orphan GPCRs had eight genetic associations, highlighting novel biology for these receptors of unknown function. We found several associations between GPCR variants and food intake phenotypes, including an association between the variants in TAS2R38 known to affect the ability to taste phenylthiocarbamide and tea intake as well as a non-additive associations between variants in TAS2R19 and TAS2R31 and coffee and tea intake. Finally, we tested whether genetic variants in ADRB2 associated with immune cell amounts and pulmonary function affect downstream signaling pathways and found that two ADRB2 haplotypes are associated with differential signaling relative to the most common haplotype. Overall, this study provides a map of genetic associations for GPCR coding variants across a wide variety of phenotypes that can inform future drug discovery efforts targeting GPCRs.

Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants

“…Deleteriousness can be approximated with available information on sequence conservation and molecular functionality, but such data are rarely combined. Furthermore, even a strong association between a mutation and a clinical trait does not provide specific information on the corresponding changes in protein function and/or structure. , Since just a single genetic variant can change the local structure of a protein or its interactions with other proteins, it can actually have various functional effects . Thus, genetic variants could be instrumental in deciphering molecular determinants and pathways.…”