Abstract
Epigenetic regulation of gene expression has been shown to change over time and may be associated with environmental exposures in common complex traits. Age-related hearing impairment is a complex disorder, known to be heritable, with heritability estimates of 57–70%. Epigenetic regulation might explain the observed difference in age of onset and magnitude of hearing impairment with age. Epigenetic epidemiology studies using unrelated samples can be limited in their ability to detect small effects, and recent epigenetic findings in twins underscore the power of this well matched study design. We investigated the association between venous blood DNA methylation epigenome-wide and hearing ability. Pure-tone audiometry (PTA) and Illumina HumanMethylation array data were obtained from female twin volunteers enrolled in the TwinsUK register. Two study groups were explored: first, an epigenome-wide association scan (EWAS) was performed in a discovery sample (n = 115 subjects, age range: 47–83 years, Illumina 27 k array), then replication of the top ten associated probes from the discovery EWAS was attempted in a second unrelated sample (n = 203, age range: 41–86 years, Illumina 450 k array). Finally, a set of monozygotic (MZ) twin pairs (n = 21 pairs) within the discovery sample (Illumina 27 k array) was investigated in more detail in an MZ discordance analysis. Hearing ability was strongly associated with DNA methylation levels in the promoter regions of several genes, including TCF25 (cg01161216, p = 6.6×10−6), FGFR1 (cg15791248, p = 5.7×10−5) and POLE (cg18877514, p = 6.3×10−5). Replication of these results in a second sample confirmed the presence of differential methylation at TCF25 (p(replication) = 6×10−5) and POLE (p(replication) = 0.016). In the MZ discordance analysis, twins' intrapair difference in hearing ability correlated with DNA methylation differences at ACP6 (cg01377755, r = −0.75, p = 1.2×10−4) and MEF2D (cg08156349, r = −0.75, p = 1.4×10−4). Examination of gene expression in skin, suggests an influence of differential methylation on expression, which may account for the variation in hearing ability with age.
Highlights
The term epigenetics [1] refers to the regulation of gene expression primarily by DNA methylation and changes to DNA folding
Changes in DNA methylation have been associated with increasing age and age-related disorders [11]
Epigenetic changes at a number of genes that were associated with hearing ability, and two of these changes in genes transcription factor 25 (TCF25) and polymerase epsilon catalytic subunit (POLE) replicated in an independent sample
Summary
The term epigenetics [1] refers to the regulation of gene expression primarily by DNA methylation and changes to DNA folding. Epigenetics plays an important role in gene expression regulation and cell differentiation in the developing organism [2,3]. DNA methylation is one of the most commonly studied epigenetic changes and involves the addition of a methyl-group to the 5th carbon molecule of a cytosine base, generating 5-methyl-cytosine. This stable modification occurs primarily at the CpG dinucleotide, but has been detected at CpH sides, where H can stand for C, A or T. DNA methyl-transferases are responsible for de novo methylation of DNA [6] and facilitating stable transmission of epigenetic marks during cell division [7]
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