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Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Parsa AkbariOlukayode A SosinaJonas BovijnKarl LandheerJonas B NielsenMinhee KimSenem AykulTanima DeMary E HaasGeorge HindyNan LinIan R DinsmoreJonathan Z LuoStefanie HectorsBenjamin GeraghtyMary GerminoLampros PanagisProdromos ParasoglouJohnathon R WallsGabor HalaszGurinder S Atwalnull nullnull nullMarcus JonesMichelle G LeBlancChristopher D StillDavid J CareyAlice GiontellaMarju Orho-MelanderJaime Berumen-CamposPablo Kuri-MoralesJesus AlegreJason M TorresJonathan R EmbersonRory CollinsDaniel James RaderBrian ZambrowiczAndrew J MurphySuganthi BalasubramanianJohn D OvertonJeffrey G ReidAlan R ShuldinerMichael CantorGonçalo R AbecasisManuel A R FerreiraMark W SleemanViktoria GusarovaJudith AltarejosCharles HarrisAris N EconomidesVincent IdoneKatia KaralisGiusy Della GattaTooraj MirshahiGeorge D YancopoulosOlle MelanderJonathan MarchiniRoberto Tapia-ConyerAdam E LockeAris BarasNiek VerweijLuca A Lotta
Published in: Nature communications (2022)
Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10 -09 ), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.
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