O03 Genetic impacts on the skin methylome

Abstract Introduction and aims DNA methylation at CpG dinucleotides is a dynamic epigenetic mechanism that has been linked to numerous skin phenotypes and diseases. Previous studies in blood show that a substantial proportion of the human DNA methylome exhibits evidence for genetic influence, and that 15–17% of narrow-sense methylation heritability is explained by genetic variants, or methylation quantitative trait loci (meQTLs). However, no genome-wide meQTL studies have previously been performed in skin. The primary purpose of this work was to identify the genetic basis of DNA methylation levels in whole skin. Methods Utilizing a twin-based heritability model, we estimated DNA methylation heritability using 414 bulk skin tissue samples from healthy older female twins from the TwinsUK cohort, profiled using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, CA, USA). We then integrated genomic data for 394 of these twins to perform genome-wide meQTL analyses. Finally, we integrated these meQTL Results with skin eQTL Results from an overlapping sample (N = 664). Results Over 8.2% of measured CpG sites showed evidence for strong heritability (h2 > 0.4), with a mean additive heritability estimate of 11.07% across all tested sites. We identified 76 442 CpG sites (18.8% of measured CpG sites) associated with a meQTL in cis (< 1 MB variant-CpG distance) and 1438 (0.35%) in trans. Both CpG sites under meQTL effects, and genetic variants underlying these meQTL effects in skin, are enriched in regions previously identified from genome-wide and epigenome-wide association studies for skin-related phenotypes, including psoriasis, melanoma and vitiligo. Additionally, some meQTLs influence gene expression via mediation of expression quantitative trait loci effects in skin, including in genes linked to melanoma and psoriasis. Conclusions Our study is the first genome-wide DNA methylation heritability and meQTL analysis of whole skin, giving insights into the regulatory landscape of epigenomic variation in skin.