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

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  • Additional Information
    • Corporate Authors:
      Regeneron Genetics Center; DiscovEHR Collaboration
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
    • Publication Information:
      Publication: : Washington, DC : American Association for the Advancement of Science
      Original Publication: New York, N.Y. : [s.n.] 1880-
    • Subject Terms:
      Body Mass Index*; Exome/*genetics ; Obesity/*genetics ; Receptors, G-Protein-Coupled/*genetics; Animals ; Genetic Variation ; Humans ; Mice ; Mice, Knockout ; Sequence Analysis, DNA ; Weight Gain/genetics
    • 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.
      (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
    • Comments:
      Comment in: Science. 2021 Jul 2;373(6550):30-31. (PMID: 34210869)
      Comment in: Nat Rev Genet. 2021 Sep;22(9):549. (PMID: 34267364)
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    • Grant Information:
      P01 HL034300 United States HL NHLBI NIH HHS; P30 DK063491 United States DK NIDDK NIH HHS; MC_QA137853 United Kingdom MRC_ Medical Research Council; MC_UU_00017/2 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; UL1 TR001881 United States TR NCATS NIH HHS; R01 HL139793 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (GPR75 protein, human)
      0 (Receptors, G-Protein-Coupled)
    • Publication Date:
      Date Created: 20210702 Date Completed: 20210713 Latest Revision: 20230619
    • Publication Date:
      20231215
    • Accession Number:
      PMC10275396
    • Accession Number:
      10.1126/science.abf8683
    • Accession Number:
      34210852