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

Akbari, Parsa ; Gilani, Ankit ; Sosina, Olukayode ; Kosmicki, Jack A. ; Khrimian, Lori ; Fang, Yi Ya ; Persaud, Trikaldarshi ; Garcia, Victor ; Sun, Dylan and Li, Alexander , et al. (2021) In Science 373(6550).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science
volume
373
issue
6550
article number
eabf8683
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:34210852
  • scopus:85108992024
ISSN
0036-8075
DOI
10.1126/science.abf8683
language
English
LU publication?
yes
id
3d414414-f96d-407d-ac3f-ba33611f898e
date added to LUP
2021-08-23 10:59:17
date last changed
2024-09-08 22:02:21
@article{3d414414-f96d-407d-ac3f-ba33611f898e,
  abstract     = {{<p>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.</p>}},
  author       = {{Akbari, Parsa and Gilani, Ankit and Sosina, Olukayode and Kosmicki, Jack A. and Khrimian, Lori and Fang, Yi Ya and Persaud, Trikaldarshi and Garcia, Victor and Sun, Dylan and Li, Alexander and Mbatchou, Joelle and Locke, Adam E. and Benner, Christian and Verweij, Niek and Lin, Nan and Hossain, Sakib and Agostinucci, Kevin and Pascale, Jonathan V. and Dirice, Ercument and Dunn, Michael and Kraus, William E. and Shah, Svati H. and Chen, Yii Der I. and Rotter, Jerome I. and Rader, Daniel J. and Melander, Olle and Still, Christopher D. and Mirshahi, Tooraj and Carey, David J. and Berumen-Campos, Jaime and Kuri-Morales, Pablo and Alegre-Díaz, Jesus and Torres, Jason M. and Emberson, Jonathan R. and Collins, Rory and Balasubramanian, Suganthi and Hawes, Alicia and Jones, Marcus and Zambrowicz, Brian and Murphy, Andrew J. and Paulding, Charles and Coppola, Giovanni and Overton, John D. and Reid, Jeffrey G. and Shuldiner, Alan R. and Cantor, Michael and Kang, Hyun M. and Abecasis, Goncalo R. and Karalis, Katia and Economides, Aris N. and Marchini, Jonathan and Yancopoulos, George D and Sleeman, Mark W. and Altarejos, Judith and Gatta, Giusy Della and Tapia-Conyer, Roberto and Schwartzman, Michal L. and Baras, Aris and Ferreira, Manuel A. R. and Lotta, Luca A.}},
  issn         = {{0036-8075}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{6550}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science}},
  title        = {{Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity}},
  url          = {{http://dx.doi.org/10.1126/science.abf8683}},
  doi          = {{10.1126/science.abf8683}},
  volume       = {{373}},
  year         = {{2021}},
}