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

Authors :
Akbari P
Sosina OA
Bovijn J
Landheer K
Nielsen JB
Kim M
Aykul S
De T
Haas ME
Hindy G
Lin N
Dinsmore IR
Luo JZ
Hectors S
Geraghty B
Germino M
Panagis L
Parasoglou P
Walls JR
Halasz G
Atwal GS
Jones M
LeBlanc MG
Still CD
Carey DJ
Giontella A
Orho-Melander M
Berumen J
Kuri-Morales P
Alegre-Díaz J
Torres JM
Emberson JR
Collins R
Rader DJ
Zambrowicz B
Murphy AJ
Balasubramanian S
Overton JD
Reid JG
Shuldiner AR
Cantor M
Abecasis GR
Ferreira MAR
Sleeman MW
Gusarova V
Altarejos J
Harris C
Economides AN
Idone V
Karalis K
Della Gatta G
Mirshahi T
Yancopoulos GD
Melander O
Marchini J
Tapia-Conyer R
Locke AE
Baras A
Verweij N
Lotta LA
Source :
Nature communications [Nat Commun] 2022 Aug 23; Vol. 13 (1), pp. 4844. Date of Electronic Publication: 2022 Aug 23.
Publication Year :
2022

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 <superscript>-09</superscript> ), 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.<br /> (© 2022. The Author(s).)

Details

Language :
English
ISSN :
2041-1723
Volume :
13
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
35999217
Full Text :
https://doi.org/10.1038/s41467-022-32398-7