TY - JOUR
T1 - Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity
AU - Akbari, Parsa
AU - Gilani, Ankit
AU - Sosina, Olukayode
AU - Kosmicki, Jack A.
AU - Khrimian, Lori
AU - Fang, Yi Ya
AU - Persaud, Trikaldarshi
AU - Garcia, Victor
AU - Sun, Dylan
AU - Li, Alexander
AU - Mbatchou, Joelle
AU - Locke, Adam E.
AU - Benner, Christian
AU - Verweij, Niek
AU - Lin, Nan
AU - Hossain, Sakib
AU - Agostinucci, Kevin
AU - Pascale, Jonathan V.
AU - Dirice, Ercument
AU - Dunn, Michael
AU - Regeneron Genetics Center
AU - DiscovEHR Collaboration
AU - Kraus, William E.
AU - Shah, Svati H.
AU - Chen, Yii Der I.
AU - Rotter, Jerome I.
AU - Rader, Daniel J.
AU - Melander, Olle
AU - Still, Christopher D.
AU - Mirshahi, Tooraj
AU - Carey, David J.
AU - Berumen-Campos, Jaime
AU - Kuri-Morales, Pablo
AU - Alegre-Díaz, Jesus
AU - Torres, Jason M.
AU - Emberson, Jonathan R.
AU - Collins, Rory
AU - Balasubramanian, Suganthi
AU - Hawes, Alicia
AU - Jones, Marcus
AU - Zambrowicz, Brian
AU - Murphy, Andrew J.
AU - Paulding, Charles
AU - Coppola, Giovanni
AU - Overton, John D.
AU - Reid, Jeffrey G.
AU - Shuldiner, Alan R.
AU - Cantor, Michael
AU - Kang, Hyun M.
AU - Abecasis, Goncalo R.
AU - Karalis, Katia
AU - Economides, Aris N.
AU - Marchini, Jonathan
AU - Yancopoulos, George D
AU - Sleeman, Mark W.
AU - Altarejos, Judith
AU - Gatta, Giusy Della
AU - Tapia-Conyer, Roberto
AU - Schwartzman, Michal L.
AU - Baras, Aris
AU - Ferreira, Manuel A. R.
AU - Lotta, Luca A.
PY - 2021/7/2
Y1 - 2021/7/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108992024&partnerID=8YFLogxK
U2 - 10.1126/science.abf8683
DO - 10.1126/science.abf8683
M3 - Article
C2 - 34210852
AN - SCOPUS:85108992024
SN - 0036-8075
VL - 373
JO - Science
JF - Science
IS - 6550
M1 - eabf8683
ER -
