NYMC Faculty Publications

Sequencing of 640,000 Exomes Identifies GPR75 Variants Associated with Protection from Obesity

Author Type(s)

Faculty

DOI

10.1126/science.abf8683

Journal Title

Science

First Page

eabf8683

Last Page

eabf8683

Document Type

Article

Publication Date

7-2-2021

Department

Pharmacology

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.

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