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

Publication ,  Journal Article
Akbari, P; Gilani, A; Sosina, O; Kosmicki, JA; Khrimian, L; Fang, Y-Y; Persaud, T; Garcia, V; Sun, D; Li, A; Mbatchou, J; Locke, AE; Lin, N ...
Published in: Science
July 2, 2021

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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Published In

Science

DOI

EISSN

1095-9203

Publication Date

July 2, 2021

Volume

373

Issue

6550

Location

United States

Related Subject Headings

  • Weight Gain
  • Sequence Analysis, DNA
  • Receptors, G-Protein-Coupled
  • Obesity
  • Mice, Knockout
  • Mice
  • Humans
  • Genetic Variation
  • General Science & Technology
  • Exome
 

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Akbari, P., Gilani, A., Sosina, O., Kosmicki, J. A., Khrimian, L., Fang, Y.-Y., … Lotta, L. A. (2021). Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science, 373(6550). https://doi.org/10.1126/science.abf8683
Akbari, Parsa, Ankit Gilani, Olukayode Sosina, Jack A. Kosmicki, Lori Khrimian, Yi-Ya Fang, Trikaldarshi Persaud, et al. “Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity.Science 373, no. 6550 (July 2, 2021). https://doi.org/10.1126/science.abf8683.
Akbari P, Gilani A, Sosina O, Kosmicki JA, Khrimian L, Fang Y-Y, et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science. 2021 Jul 2;373(6550).
Akbari, Parsa, et al. “Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity.Science, vol. 373, no. 6550, July 2021. Pubmed, doi:10.1126/science.abf8683.
Akbari P, Gilani A, Sosina O, Kosmicki JA, Khrimian L, Fang Y-Y, Persaud T, Garcia V, Sun D, Li A, Mbatchou J, Locke AE, Benner C, Verweij N, Lin N, Hossain S, Agostinucci K, Pascale JV, Dirice E, Dunn M, Regeneron Genetics Center, DiscovEHR Collaboration, Kraus WE, Shah SH, Chen Y-DI, Rotter JI, Rader DJ, Melander O, Still CD, Mirshahi T, Carey DJ, Berumen-Campos J, Kuri-Morales P, Alegre-Díaz J, Torres JM, Emberson JR, Collins R, Balasubramanian S, Hawes A, Jones M, Zambrowicz B, Murphy AJ, Paulding C, Coppola G, Overton JD, Reid JG, Shuldiner AR, Cantor M, Kang HM, Abecasis GR, Karalis K, Economides AN, Marchini J, Yancopoulos GD, Sleeman MW, Altarejos J, Della Gatta G, Tapia-Conyer R, Schwartzman ML, Baras A, Ferreira MAR, Lotta LA. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science. 2021 Jul 2;373(6550).
Journal cover image

Published In

Science

DOI

EISSN

1095-9203

Publication Date

July 2, 2021

Volume

373

Issue

6550

Location

United States

Related Subject Headings

  • Weight Gain
  • Sequence Analysis, DNA
  • Receptors, G-Protein-Coupled
  • Obesity
  • Mice, Knockout
  • Mice
  • Humans
  • Genetic Variation
  • General Science & Technology
  • Exome