DNA methylation QTL analysis identifies new regulators of human longevity.
Aged, 80 and over
Apolipoproteins E
/ genetics
DNA Methylation
/ genetics
DNA-Binding Proteins
/ genetics
Endonucleases
/ genetics
Epigenesis, Genetic
/ genetics
Epigenome
/ genetics
Female
Gene Expression Regulation
/ genetics
Genome, Human
/ genetics
Humans
Longevity
/ genetics
Male
Membrane Transport Proteins
/ genetics
Mitochondrial Precursor Protein Import Complex Proteins
Nectins
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
08 05 2020
08 05 2020
Historique:
received:
06
06
2019
revised:
01
01
2020
accepted:
11
02
2020
pubmed:
12
3
2020
medline:
5
8
2021
entrez:
12
3
2020
Statut:
ppublish
Résumé
Human longevity is a complex trait influenced by both genetic and environmental factors, whose interaction is mediated by epigenetic mechanisms like DNA methylation. Here, we generated genome-wide whole-blood methylome data from 267 individuals, of which 71 were long-lived (90-104 years), by applying reduced representation bisulfite sequencing. We followed a stringent two-stage analysis procedure using discovery and replication samples to detect differentially methylated sites (DMSs) between young and long-lived study participants. Additionally, we performed a DNA methylation quantitative trait loci analysis to identify DMSs that underlie the longevity phenotype. We combined the DMSs results with gene expression data as an indicator of functional relevance. This approach yielded 21 new candidate genes, the majority of which are involved in neurophysiological processes or cancer. Notably, two candidates (PVRL2, ERCC1) are located on chromosome 19q, in close proximity to the well-known longevity- and Alzheimer's disease-associated loci APOE and TOMM40. We propose this region as a longevity hub, operating on both a genetic (APOE, TOMM40) and an epigenetic (PVRL2, ERCC1) level. We hypothesize that the heritable methylation and associated gene expression changes reported here are overall advantageous for the LLI and may prevent/postpone age-related diseases and facilitate survival into very old age.
Identifiants
pubmed: 32160291
pii: 5803132
doi: 10.1093/hmg/ddaa033
pmc: PMC7206852
doi:
Substances chimiques
ApoE protein, human
0
Apolipoproteins E
0
DNA-Binding Proteins
0
Membrane Transport Proteins
0
Mitochondrial Precursor Protein Import Complex Proteins
0
NECTIN2 protein, human
0
Nectins
0
TOMM40 protein, human
0
ERCC1 protein, human
EC 3.1.-
Endonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1154-1167Subventions
Organisme : NIA NIH HHS
ID : R01 AG037985
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press.
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