Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity
Open accessAbstract
How genes affect human obesity: Obesity is linked to many human diseases, including diabetes, cancer, and heart disease. There is thus great interest in understanding how genes predispose individuals to, or protect individuals from, obesity. Akbari et al. sequenced more than 600,000 exomes from the United Kingdom, the United States, and Mexico and identified 16 rare coding variants (see the Perspective by Yeo and O'Rahilly). Some of the alleles associated with body mass index (BMI) were brain-expressed G protein–coupled receptors. One variant allele was found in Mexican populations at low frequency and was associated with lower BMI. Deletion of this gene in mice resulted in a resistance to weight gain, suggesting that this gene provides an avenue of study for the prevention or treatment of obesity. Science , abf8683, this issue p. eabf8683 ; see also abh3556, p. 30
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Genetic preclinical models support the role of GIPR antagonism as a method to promote weight loss and prevent weight gain.
“and genetic preclinical models30,31,39,40 support the role of GIPR antagonism as a method to promote weight loss and prevent weight gain.”
From A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings (2024) · cites this paper as [39]
The ‘Genomic insights at other BMI-associated GPCRs’ section reports that GIPR loss-of-function variants are associated with lower BMI and obesity risk in humans, and confirms impaired signaling in cell experiments. It does not report a GIPR genetic preclinical model or show that GIPR antagonism promotes weight loss or prevents weight gain; the mouse weight-gain experiment concerns Gpr75, not Gipr (Gpr75 deletion section; page not provided). (LLM, conf=0.88)
Experimental — accuracy not yet measuredInitial reports that GIPR null mice are protected from diet-induced obesity have been supported by preclinical studies in rodents and non-human primates that GIPR antagonism induces additive weight loss when combined with GLP-1R agonism, and human genetics data that loss-of-function GIPR variants associate with reduced adiposity.
“Initial reports that GIPR null mice [64] are protected from diet-induced obesity have been supported by preclinical studies in rodents and non-human primates that GIPR antagonism induces additive weight loss when combined with GLP-1R agonism [32,67], and human genetics data that loss-of-function GIPR variants associate with reduced adiposity [68].”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [68]
Individuals with at least one inactive copy of GPR75 gene have lower body mass index and about 50% lower risk of obesity.
“Individuals with at least one inactive copy of GPR75 gene have lower body mass index and about 50% lower risk of obesity [186].”
From Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022 (2022) · cites this paper as [186]
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References 81 · Cited by 276
- Authors
- Akbari, P., Gilani, A., Sosina, O., Kosmicki, J. A., Khrimian, L., Fang, Y.-Y., Persaud, T., Garcia, V., Sun, D., Li, A., Mbatchou, J., Locke, A. E., Benner, C., Verweij, N., Lin, N., Hossain, S., Agostinucci, K., Pascale, J. V., Dirice, E., Dunn, M., Regeneron Genetics Center, DiscovEHR Collaboration, Kraus, W. E., Shah, S. H., Chen, Y.-D. I., Rotter, J. I., Rader, D. J., Melander, O., Still, C. D., Mirshahi, T., Carey, D. J., Berumen-Campos, J., Kuri-Morales, P., Alegre-Díaz, J., Torres, J. M., Emberson, J. R., Collins, R., Balasubramanian, S., Hawes, A., Jones, M., Zambrowicz, B., Murphy, A. J., Paulding, C., Coppola, G., Overton, J. D., Reid, J. G., Shuldiner, A. R., Cantor, M., Kang, H. M., Abecasis, G. R., Karalis, K., Economides, A. N., Marchini, J., Yancopoulos, G. D., Sleeman, M. W., Altarejos, J., Della Gatta, G., Tapia-Conyer, R., Schwartzman, M. L., Baras, A., Ferreira, M. A. R., & Lotta, L. A.
- Affiliations
- Regeneron (United States) (US)
- New York Medical College (US)
- Duke Medical Center (US)
- The Lundquist Institute (US)
- University of Pennsylvania (US)
- Lund University (SE)
- Geisinger Health System (US)
- Universidad Nacional Autónoma de México (MX)
- Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, 4360 Ciudad de México, Mexico.
- University of Oxford (GB)
- Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
- Corresponding author
- Akbari, Parsa
- Gilani, Ankit
- Sosina, Olukayode
- Tapia-Conyer, Roberto
- Schwartzman, Michal L.
- Baras, Aris
- Ferreira, Manuel A. R.
- Lotta, Luca A.
- ORCID
- Akbari, Parsa
- Gilani, Ankit
- Sosina, Olukayode
- Kosmicki, Jack A.
- Khrimian, Lori
- Persaud, Trikaldarshi
- Garcia, Victor
- Sun, Dylan
- Li, Alexander
- Mbatchou, Joelle
- Locke, Adam E.
- Benner, Christian
- Verweij, Niek
- Agostinucci, Kevin
- Pascale, Jonathan V.
- Dirice, Ercument
- Kraus, William E.
- Shah, Svati H.
- Chen, Yii-Der I.
- Rotter, Jerome I.
- Rader, Daniel J.
- Melander, Olle
- Still, Christopher D.
- Mirshahi, Tooraj
- Carey, David J.
- Berumen-Campos, Jaime
- Kuri-Morales, Pablo
- Alegre-Díaz, Jesus
- Torres, Jason M.
- Emberson, Jonathan R.
- Collins, Rory
- Balasubramanian, Suganthi
- Zambrowicz, Brian
- Murphy, Andrew J.
- Paulding, Charles
- Coppola, Giovanni
- Overton, John D.
- Reid, Jeffrey G.
- Shuldiner, Alan R.
- Cantor, Michael
- Kang, Hyun M.
- Karalis, Katia
- Economides, Aris N.
- Marchini, Jonathan
- Sleeman, Mark W.
- Altarejos, Judith
- Della Gatta, Giusy
- Tapia-Conyer, Roberto
- Schwartzman, Michal L.
- Baras, Aris
- Ferreira, Manuel A. R.
- Lotta, Luca A.
- Venue
- Science
- Published
- 2021-07-02
- Volume
- 373
- Issue
- 6550
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC10275396
- OpenAlex
- W3174336210
- Cited by
- 276
- References
- 81
- Citations by year
- 2026: 42 · 2025: 54 · 2024: 63 · 2023: 53 · 2022: 52 · 2021: 12
- FWCI
- 25.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- other-oa
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, other-oa)
- Touro Scholar (Touro College) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institutes of Health (HL034300, HL139793, HL139793-1S)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491)
- National Center for Advancing Translational Sciences (UL1TR001881)
- Regeneron Pharmaceuticals
- Wellcome
- Ministry of Health Mexico
- Medical Research Council
- British Heart Foundation
- Cancer Research UK
- Consejo Nacional de Ciencia y Tecnología
- Nuffield Department of Population Health, University of Oxford
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- GPR75, obesity, body mass index, rare coding variants, exome sequencing, Mexican population, obesity prevention
- MeSH terms
- Animals, Humans, Obesity, Genetic Variation, Weight Gain, Body Mass Index, Sequence Analysis, DNA, Mice, Knockout, Receptors, G-Protein-Coupled, Mice, Exome
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