Local CpG density affects the trajectory and variance of age-associated DNA methylation changes

Jon Higham, Lyndsay Kerr, Qian Zhang, Rosie Walker, Sarah Harris, David M. Howard, Emma Hawkins, Anca-larisa Sandu, J Douglas Steele, Gordon D. Waiter, Alison D Murray, Kathryn Louise Evans, Andrew M McIntosh, Peter M. Visscher, Ian J Deary, Simon R. Cox, Duncan Sproul*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background
DNA methylation is an epigenetic mark associated with the repression of gene promoters.
Its pattern in the genome is disrupted with age and these changes can be used to
statistically predict age with epigenetic clocks. Altered rates of aging inferred from these
clocks are observed in human disease. However, the molecular mechanisms underpinning
age-associated DNA methylation changes remain unknown. Local DNA sequence can
program steady-state DNA methylation levels, but how it influences age-associated
methylation changes is unknown.
Results
We analyse longitudinal human DNA methylation trajectories at 345,895 CpGs from 600
individuals aged between 67 and 80 to understand the factors responsible for ageassociated epigenetic changes at individual CpGs. We show that changes in methylation
with age occur at 182,760 loci largely independently of variation in cell type proportions.
These changes are especially apparent at 8,322 low CpG density loci. Using SNP data from
the same individuals, we demonstrate that methylation trajectories are affected by local
sequence polymorphisms at 1,487 low CpG density loci. More generally, we find that low
CpG density regions are particularly prone to change and do so variably between individuals
in people aged over 65. This differs from the behaviour of these regions in younger
individuals where they predominantly lose methylation.
Conclusions
Our results, which we reproduce in two independent groups of individuals, demonstrate
that local DNA sequence influences age- associated DNA methylation changes in humans in
vivo. We suggest that this occurs because interactions between CpGs reinforce maintenance
of methylation patterns in CpG dense regions.
Original languageEnglish
JournalGenome Biology
Publication statusPublished - 17 Oct 2022

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