Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Akbari, P. ; Giontella, A. LU orcid ; Orho-Melander, M. LU ; Melander, O. LU orcid and Lotta, Luca A. (2022) In Nature Communications 13(1).
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 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for... (More)
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. © 2022. The Author(s). (Less)
Please use this url to cite or link to this publication:
author
; ; ; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
13
issue
1
article number
4844
publisher
Nature Publishing Group
external identifiers
  • scopus:85136390442
  • pmid:35999217
ISSN
2041-1723
DOI
10.1038/s41467-022-32398-7
language
English
LU publication?
yes
id
035f57d6-e6d1-4f48-bc1c-54603b03f126
date added to LUP
2022-09-16 10:28:03
date last changed
2025-04-04 14:50:39
@article{035f57d6-e6d1-4f48-bc1c-54603b03f126,
  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 × 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. © 2022. The Author(s).}},
  author       = {{Akbari, P. and Giontella, A. and Orho-Melander, M. and Melander, O. and Lotta, Luca A.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes}},
  url          = {{http://dx.doi.org/10.1038/s41467-022-32398-7}},
  doi          = {{10.1038/s41467-022-32398-7}},
  volume       = {{13}},
  year         = {{2022}},
}