Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity PMID: 34210852

Target-related Cytokines

2026-09-23

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

Science. 2021 Jul 2;373(6550):eabf8683. doi: 10.1126/science.abf8683.

Parsa Akbari ^# ¹ , Ankit Gilani ^# ² , Olukayode Sosina ^# ¹ , Jack A Kosmicki ¹ , Lori Khrimian ³ , Yi-Ya Fang ³ , Trikaldarshi Persaud ¹ , Victor Garcia ² , Dylan Sun ¹ , Alexander Li ¹ , Joelle Mbatchou ¹ , Adam E Locke ¹ , Christian Benner ¹ , Niek Verweij ¹ , Nan Lin ¹ , Sakib Hossain ² , Kevin Agostinucci ² , Jonathan V Pascale ² , Ercument Dirice ² , Michael Dunn ³ , Regeneron Genetics Center , DiscovEHR Collaboration , William E Kraus ⁴ ⁵ , Svati H Shah ⁶ ⁷ , Yii-Der I Chen ⁸ , Jerome I Rotter ⁸ , Daniel J Rader ⁹ , Olle Melander ¹⁰ ¹¹ , Christopher D Still ¹² , Tooraj Mirshahi ¹² , David J Carey ¹² , Jaime Berumen-Campos ¹³ , Pablo Kuri-Morales ¹³ , Jesus Alegre-Díaz ¹³ , Jason M Torres ¹⁴ , Jonathan R Emberson ¹⁴ , Rory Collins ¹⁴ , Suganthi Balasubramanian ¹ , Alicia Hawes ¹ , Marcus Jones ¹ , Brian Zambrowicz ³ , Andrew J Murphy ³ , Charles Paulding ¹ , Giovanni Coppola ¹ , John D Overton ¹ , Jeffrey G Reid ¹ , Alan R Shuldiner ¹ , Michael Cantor ¹ , Hyun M Kang ¹ , Goncalo R Abecasis ¹ , Katia Karalis ¹ , Aris N Economides ¹ ³ , Jonathan Marchini ¹ , George D Yancopoulos ³ , Mark W Sleeman ³ , Judith Altarejos ³ , Giusy Della Gatta ¹ , Roberto Tapia-Conyer ^# ¹³ , Michal L Schwartzman ^# ² , Aris Baras ^# ¹⁵ , Manuel A R Ferreira ^# ¹ , Luca A Lotta ^# ¹⁵

Affiliations

1. Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
2. Department of Pharmacology and Medicine, New York Medical College School of Medicine, Valhalla, NY 10595, USA.
3. Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
4. Division of Cardiology, Duke University Medical Center, Durham, NC 27710, USA.
5. Duke Center for Living, Duke University Medical Center, Durham, NC 27705, USA.
6. Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
7. Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27701, USA.
8. Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
9. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
10. Department of Clinical Sciences Malmö, Lund University, 221 00 Malmö, Sweden.
11. Department of Emergency and Internal Medicine, Skåne University Hospital, 214 28, Malmö, Sweden.
12. Geisinger Obesity Institute, Geisinger Health System, Danville, PA 17882, USA.
13. Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico.
14. Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, England, UK.
15. Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA. [email protected] [email protected].
# Contributed equally.

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.