| Title: | Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes |
| Journal: | Nature Communications |
| Published: | 23 Aug 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35999217/ |
| DOI: | https://doi.org/10.1038/s41467-022-32398-7 |
| URL: | https://www.nature.com/articles/s41467-022-32398-7 |
Publication 14
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Abstract
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 x 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 betaE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.62 Authors
- Parsa Akbari
- Olukayode A. Sosina
- Jonas Bovijn
- Karl Landheer
- Jonas B. Nielsen
- Minhee Kim
- Senem Aykul
- Tanima De
- Mary E. Haas
- George Hindy
- Nan Lin
- Ian R. Dinsmore
- Jonathan Z. Luo
- Stefanie Hectors
- Benjamin Geraghty
- Mary Germino
- Lampros Panagis
- Prodromos Parasoglou
- Johnathon R. Walls
- Gabor Halasz
- Gurinder S. Atwal
- Regeneron Genetics Center
- DiscovEHR Collaboration
- Marcus Jones
- Michelle G. LeBlanc
- Christopher D. Still
- David J. Carey
- Alice Giontella
- Marju Orho-Melander
- Jaime Berumen
- Pablo Kuri-Morales
- Jesus Alegre-Díaz
- Jason M. Torres
- Jonathan R. Emberson
- Rory Collins
- Daniel J. Rader
- Brian Zambrowicz
- Andrew J. Murphy
- Suganthi Balasubramanian
- John D. Overton
- Jeffrey G. Reid
- Alan R. Shuldiner
- Michael Cantor
- Goncalo R. Abecasis
- Manuel A. R. Ferreira
- Mark W. Sleeman
- Viktoria Gusarova
- Judith Altarejos
- Charles Harris
- Aris N. Economides
- Vincent Idone
- Katia Karalis
- Giusy Della Gatta
- Tooraj Mirshahi
- George D. Yancopoulos
- Olle Melander
- Jonathan Marchini
- Roberto Tapia-Conyer
- Adam E. Locke
- Aris Baras
- Niek Verweij
- Luca A. Lotta