G protein-coupled receptors (GPCRs) drive an array of critical physiological functions and are an important class of drug targets, though a map of which GPCR genetic variants are associated with phenotypic variation is lacking. We performed a phenome-wide association analysis for 269 common protein-altering variants in 156 GPCRs and 275 phenotypes, including disease outcomes and diverse quantitative measurements, using 337,205 UK Biobank participants and identified 138 associations. We discovered novel associations between GPCR variants and migraine risk, hypothyroidism, and dietary consumption. We also demonstrated experimentally that variants in the β2 adrenergic receptor (ADRB2) associated with immune cell counts and pulmonary function and variants in the gastric inhibitory polypeptide receptor (GIPR) associated with food intake and body size affect downstream signaling pathways. Overall, this study provides a map of genetic associations for GPCR coding variants across a wide variety of phenotypes, which can inform future drug discovery efforts targeting GPCRs.

中文翻译：

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英国生物库中337,205名个体的GPCR基因中常见的改变蛋白质的变体具有医学相关性

尽管缺乏GPCR遗传变异与表型变异相关的图谱，但G蛋白偶联受体（GPCR）可以驱动一系列关键的生理功能，并且是一类重要的药物靶标。我们使用337,205个英国生物库参与者，对156种GPCR和275种表型中的269种常见蛋白质改变变体进行了全表型关联分析，包括疾病结果和多种定量测量，并确定了138个关联。我们发现GPCR变异与偏头痛风险，甲状腺功能减退症和饮食摄入之间存在新型关联。我们还通过实验证明，β2肾上腺素能受体（ADRB2）的变异与免疫细胞计数和肺功能相关，胃抑制多肽受体（GIPR）的变异与食物摄入和体重相关，会影响下游信号通路。总体而言，这项研究提供了跨越多种表型的GPCR编码变体的遗传关联图，这可以为将来针对GPCR的药物开发工作提供信息。