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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; 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
Nature communications, 08/2022, Letnik: 13, Številka: 1Journal Article
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 ), 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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