DNA methylation QTL analysis identifies new regulators of human longevity

Silke Szymczak, Janina Dose, Guillermo G Torres, Femke-Anouska Heinsen, Geetha Venkatesh, Paul Datlinger, Marianne Nygaard, Jonas Mengel-From, Friederike Flachsbart, Wolfram Klapper, Kaare Christensen, Wolfgang Lieb, Stefan Schreiber, Robert Häsler, Christoph Bock, Andre Franke, Almut Nebel

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind29
Udgave nummer7
Sider (fra-til)1154-1167
ISSN0964-6906
DOI
StatusUdgivet - 8. maj 2020

Bibliografisk note

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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