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

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.

• Authors: 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, Giusy Della Gatta, Roberto Tapia-Conyer, Michal L Schwartzman, Aris Baras, Manuel A R Ferreira, Luca A Lotta
• Journal: Science (New York, N.Y.) (Science) Vol. 373 Issue 6550 (07 02 2021) ISSN: 1095-9203 [Electronic] United States
• PMID: 34210852 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• GPR75 protein, human
• Receptors, G-Protein-Coupled

Topics

• Animals
• Body Mass Index
• Exome (genetics)
• Genetic Variation
• Humans
• Mice
• Mice, Knockout
• Obesity (genetics)
• Receptors, G-Protein-Coupled (genetics)
• Sequence Analysis, DNA
• Weight Gain (genetics)