Background: Aging is a complex biological process that involves numerous changes at various levels through remodelling of multiple biological processes and regulatory mechanisms including epigenetics. Recent analysis of the DNA methylome has reported large numbers of epigenetic markers associated with human aging. Validation and characterization of the significant findings are necessary both for obtaining reliable results and for better describing the age-associated epigenetic modifications. Methods: Based on genome-wide DNA methylation data measured in a large collection of older individuals in the Lothian Birth Cohorts of 1921 and 1936, we performed an association study to identify age-associated CpGs and replicated the findings in two independent cohorts of Danish twins. The double-replicated CpGs were characterized by distribution over gene regions and by their location in relation to CpG islands conditional on their age-dependent patterns of methylation status. The replicated CpGs were further characterized by their involvement in gene-sets or canonical pathways to study their functional implications. Results: We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWER<0.05. The double-replication resulted in 5,168 CpGs with more than 60% displaying decreased methylation with increasing age. The replicated CpGs were characterized by high concentration of age-methylated CpGs at 1stExon and TSS200 and a dominant pattern of age-demethylated CpGs at other gene regions, and by overwhelming age-related methylation in CpG island and demethylation at shore/shelf and open sea. Biological pathway analysis showed that age-dependent methylations were especially involved in cellular signalling activities while demethylations were particularly related to functions of the extracellular matrix. Conclusion: Extensive epigenetic remodelling in the DNA methylome could be involved in the aging process. The identified age-methylated and demethylated sites displayed differential distribution patterns over genomic regions and were involved in biological pathways closely related to aging phenotypes and age-related diseases.
|Status||Udgivet - 2017|
|Begivenhed||67th Annual Meeting of the American Society of Human Genetics - Orlando|
Varighed: 17. okt. 2017 → 22. okt. 2017
Konferencens nummer: 67
|Konference||67th Annual Meeting of the American Society of Human Genetics|
|Periode||17/10/2017 → 22/10/2017|