The burden of rare protein-truncating genetic variants on human lifespan.
Nat Aging
; 2(4): 289-294, 2022 04.
Article
de En
| MEDLINE
| ID: mdl-37117740
ABSTRACT
Genetic predisposition has been shown to contribute substantially to the age at which we die. Genome-wide association studies (GWASs) have linked more than 20 loci to phenotypes related to human lifespan1. However, little is known about how lifespan is impacted by gene loss of function. Through whole-exome sequencing of 352,338 UK Biobank participants of European ancestry, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified four exome-wide significant (P < 4.2 × 10-7) human lifespan genes, BRCA1, BRCA2, ATM and TET2. Gene and gene-set, PTV-burden, phenome-wide association studies support known roles of these genes in cancer to impact lifespan at the population level. The TET2 PTV burden was associated with a lifespan through somatic mutation events presumably due to clonal hematopoiesis. The overlap between PTV burden and common variant-based lifespan GWASs was modest, underscoring the value of exome sequencing in well-powered biobank cohorts to complement GWASs for identifying genes underlying complex traits.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Étude d'association pangénomique
/
Longévité
Limites:
Humans
Langue:
En
Journal:
Nat Aging
Année:
2022
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique