Nature communications · 2022

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

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Akbari Parsa, Sosina Olukayode A, Bovijn Jonas, Landheer Karl, Nielsen Jonas B, Kim Minhee, Aykul Senem, De Tanima, Haas Mary E, Hindy George, Lin Nan, Dinsmore Ian R, Luo Jonathan Z, Hectors Stefanie, Geraghty Benjamin, Germino Mary, Panagis Lampros, Parasoglou Prodromos, Walls Johnathon R, Halasz Gabor, Atwal Gurinder S, Regeneron Genetics Center, DiscovEHR Collaboration, Jones Marcus, LeBlanc Michelle G, Still Christopher D, Carey David J, Giontella Alice, Orho-Melander Marju, Berumen Jaime, Kuri-Morales Pablo, Alegre-Díaz Jesus, Torres Jason M, Emberson Jonathan R, Collins Rory, Rader Daniel J, Zambrowicz Brian, Murphy Andrew J, Balasubramanian Suganthi, Overton John D, Reid Jeffrey G, Shuldiner Alan R, Cantor Michael, Abecasis Goncalo R, Ferreira Manuel A R, Sleeman Mark W, Gusarova Viktoria, Altarejos Judith, Harris Charles, Economides Aris N, Idone Vincent, Karalis Katia, Della Gatta Giusy, Mirshahi Tooraj, Yancopoulos George D, Melander Olle, Marchini Jonathan, Tapia-Conyer Roberto, Locke Adam E, Baras Aris, Verweij Niek, Lotta Luca A

Аннотация

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.

Предметные рубрики MeSH

Adipose Tissue Adiposity Diabetes Mellitus, Type 2 Exome Humans Inhibin-beta Subunits Mutation

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH