Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity.
Parsa AkbariAnkit GilaniOlukayode A SosinaJack A KosmickiLori KhrimianYi-Ya FangTrikaldarshi PersaudVictor GarciaDylan SunAlexander H LiJoelle MbatchouAdam E LockeChristian BennerNiek VerweijNan LinSakib HossainKevin AgostinucciJonathan V PascaleErcument DiriceMichael Dunnnull nullnull nullWilliam E KrausSvati H ShahYii-Der I ChenJerome I RotterDaniel James RaderOlle MelanderChristopher D StillTooraj MirshahiDavid J CareyJaime Berumen-CamposPablo Kuri-MoralesJesus AlegreJason M TorresJonathan R EmbersonRory CollinsSuganthi BalasubramanianAlicia HawesMarcus JonesBrian ZambrowiczAndrew J MurphyCharles PauldingGiovanni CoppolaJohn D OvertonJeffrey G ReidAlan R ShuldinerMichael CantorHyun-Min KangGoncalo R AbecasisKatia KaralisAris N EconomidesJonathan MarchiniGeorge D YancopoulosMark W SleemanJudith AltarejosGiusy Della GattaRoberto Tapia-ConyerMichal L SchwartzmanAris BarasManuel A R FerreiraLuca A LottaPublished in: Science (New York, N.Y.) (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.
Keyphrases
- weight gain
- body mass index
- copy number
- insulin resistance
- high fat diet
- birth weight
- fatty acid
- genome wide
- weight loss
- glycemic control
- high fat diet induced
- type diabetes
- metabolic syndrome
- single cell
- adipose tissue
- endothelial cells
- dna methylation
- multiple sclerosis
- blood glucose
- resting state
- protein protein
- white matter
- early onset
- binding protein
- brain injury
- small molecule