| Literature DB >> 34210852 |
Parsa Akbari1, Ankit Gilani2, Olukayode Sosina1, Roberto Tapia-Conyer3, Michal L Schwartzman2, Aris Baras4, Manuel A R Ferreira1, Luca A Lotta4, Jack A Kosmicki1, Lori Khrimian5, Yi-Ya Fang5, Trikaldarshi Persaud1, Victor Garcia2, Dylan Sun1, Alexander Li1, Joelle Mbatchou1, Adam E Locke1, Christian Benner1, Niek Verweij1, Nan Lin1, Sakib Hossain2, Kevin Agostinucci2, Jonathan V Pascale2, Ercument Dirice2, Michael Dunn5, William E Kraus6,7, Svati H Shah8,9, Yii-Der I Chen10, Jerome I Rotter10, Daniel J Rader11, Olle Melander12,13, Christopher D Still14, Tooraj Mirshahi14, David J Carey14, Jaime Berumen-Campos3, Pablo Kuri-Morales3, Jesus Alegre-Díaz3, Jason M Torres15, Jonathan R Emberson15, Rory Collins15, Suganthi Balasubramanian1, Alicia Hawes1, Marcus Jones1, Brian Zambrowicz5, Andrew J Murphy5, Charles Paulding1, Giovanni Coppola1, John D Overton1, Jeffrey G Reid1, Alan R Shuldiner1, Michael Cantor1, Hyun M Kang1, Goncalo R Abecasis1, Katia Karalis1, Aris N Economides1,5, Jonathan Marchini1, George D Yancopoulos5, Mark W Sleeman5, Judith Altarejos5, Giusy Della Gatta1.
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.Entities:
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Year: 2021 PMID： 34210852 DOI： 10.1126/science.abf8683
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728