Abstract
BackgroundIt is well-known that methylation changes occur as humans age, however, understanding how age-related changes in DNA methylation vary by sex is lacking. In this study, we characterize the effect of age on DNA methylation in a sex-specific manner and determine if these effects vary by genomic context. We used the Illumina HumanMethylation 450 K array and DNA derived from whole blood for 400 adult participants (189 males and 211 females) from Bangladesh to identify age-associated CpG sites and regions and characterize the location of these age-associated sites with respect to CpG islands (vs. shore, shelf, or open sea) and gene regions (vs. intergenic). We conducted a genome-wide search for age-associated CpG sites (among 423,604 sites) using a reference-free approach to adjust for cell type composition (the R package RefFreeEWAS) and performed an independent replication analysis of age-associated CpGs.ResultsThe number of age-associated CpGs (p < 5 x 10− 8) were 986 among men and 3479 among women of which 2027(63.8%) and 572 (64.1%) replicated (using Bonferroni adjusted p < 1.2 × 10− 5). For both sexes, age-associated CpG sites were more likely to be hyper-methylated with increasing age (compared to hypo-methylated) and were enriched in CpG islands and promoter regions compared with other locations and all CpGs on the array. Although we observed strong correlation between chronological age and previously-developed epigenetic age models (r ≈ 0.8), among our top (based on lowest p-value) age-associated CpG sites only 12 for males and 44 for females are included in these prediction models, and the median chronological age compared to predicted age was 44 vs. 51.7 in males and 45 vs. 52.1 in females.ConclusionsOur results describe genome-wide features of age-related changes in DNA methylation. The observed associations between age and methylation were generally consistent for both sexes, although the associations tended to be stronger among women. Our population may have unique age-related methylation changes that are not captured in the established methylation-based age prediction model we used, which was developed to be non-tissue-specific.
Highlights
It is well-known that methylation changes occur as humans age, understanding how agerelated changes in Deoxyribonucleic acid (DNA) methylation vary by sex is lacking
Additional file 4 shows a comparison between several RefFreeEWAS models some of which are sex-specific and some adjust for smoking
Characterization the top CpG sites for each sex in relationship to gene location In order to determine if proximity to genes was related to methylation at age-related CpGs, we examined the proportion of hyper- vs. hypo-methylation at age-related CpGs within categories defined by Illumina (i.e., within 1500 basepairs of a transcription start site (TSS1500), within 200 bp of a Transcription start site (TSS) (TSS200), in a 5′ untranslated region (UTR), in the first exon, in the gene body, in the 3′ Untranslated region (UTR), and Intergenic)
Summary
It is well-known that methylation changes occur as humans age, understanding how agerelated changes in DNA methylation vary by sex is lacking. We characterize the effect of age on DNA methylation in a sex-specific manner and determine if these effects vary by genomic context. For both sexes, ageassociated CpG sites were more likely to be hyper-methylated with increasing age (compared to hypo-methylated) and were enriched in CpG islands and promoter regions compared with other locations and all CpGs on the array. Variation in DNA methylation likely reflects variation in histone modifications, chromatin conformation, and gene expression [30], with hypo-methylation of the promoter region and hyper-methylation of the gene body often reflecting increased expression [31]
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