通过对64万个外显子组测序，研究确定与肥胖预防相关的GPR75变体，这一成果由美国再生元公司Judith Altarejos课题组经过不懈努力而取得。相关论文于2021年7月2日发表在《科学》杂志上。

研究人员对来自英国、美国和墨西哥共645,626 名个体的外显子组进行了测序，并测定了罕见编码变异与体重指数 (BMI) 的关联。研究人员发现了16个与BMI有显著关联的基因，包括五种在大脑中表达的G蛋白偶联受体（CALCR、MC4R、GIPR、GPR151和GPR75）编码基因。

在约 4/10,000个测序个体中发现存在GPR75蛋白的截断变异，并且与每平方米低1.8公斤的 BMI和杂合状态下肥胖几率降低54%相关。敲除Gpr75可减缓高脂肪饮食模型中小鼠体重增加并改善血糖控制。抑制GPR75可能为肥胖症的治疗提供新方法。

研究人员表示，人类大规模外显子组测序可以鉴定与肥胖等复杂病症相关的罕见蛋白质编码变异。

附：英文原文

Title: Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity

Author: Parsa Akbari, Ankit Gilani, Olukayode Sosina, Jack A. Kosmicki, Lori Khrimian, Yi-Ya Fang, Trikaldarshi Persaud, Victor Garcia, Dylan Sun, Alexander Li, Joelle Mbatchou, Adam E. Locke, Christian Benner, Niek Verweij, Nan Lin, Sakib Hossain, Kevin Agostinucci, Jonathan V. Pascale, Ercument Dirice, Michael Dunn, Regeneron Genetics Center, DiscovEHR Collaboration, William E. Kraus, Svati H. Shah, Yii-Der I. Chen, Jerome I. Rotter, Daniel J. Rader, Olle Melander, Christopher D. Still, Tooraj Mirshahi, David J. Carey, Jaime Berumen-Campos, Pablo Kuri-Morales, Jesus Alegre-Díaz, Jason M. Torres, Jonathan R. Emberson, Rory Collins, Suganthi Balasubramanian, Alicia Hawes, Marcus Jones, Brian Zambrowicz, Andrew J. Murphy, Charles Paulding, Giovanni Coppola, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Michael Cantor, Hyun M. Kang, Goncalo R. Abecasis, Katia Karalis, Aris N. Economides, Jonathan Marchini, George D. Yancopoulos, Mark W. Sleeman, Judith Altarejos

Issue&Volume: 2021/07/02

Abstract: 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 (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 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 Gpr75 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.

DOI: 10.1126/science.abf8683

Source: https://science.sciencemag.org/content/373/6550/eabf8683