Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
Department of Pharmacology and Medicine, New York Medical College School of Medicine, Valhalla, NY 10595, USA.
Science. 2021 Jul 2;373(6550). doi: 10.1126/science.abf8683.
Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (, , , , and ). Protein-truncating variants in were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.
大规模人类外显子组测序可以鉴定出对复杂性状（如身体肥胖）有重大影响的罕见蛋白质编码变异。我们对来自英国、美国和墨西哥的 645626 个人的外显子组进行了测序，并估计了罕见编码变异与体重指数（BMI）的关联。我们鉴定出 16 个与 BMI 具有外显子范围显著关联的基因，包括编码五个脑表达 G 蛋白偶联受体（、、、、和）的基因。在约 4/10000 测序个体中观察到 中的蛋白截断变异，与 BMI 降低 1.8 公斤/平方米和杂合状态下肥胖的几率降低 54%相关。在高脂肪饮食模型中，小鼠中的 敲除导致对体重增加的抵抗力和改善的血糖控制。GPR75 的抑制可能为肥胖提供一种治疗策略。
