Abstract：
Whole-skin DNA methylation variation has been implicated in several diseases, including melanoma, but its genetic basis has not yet been fully characterized. Using bulk skin tissue samples from 414 healthy female UK twins, we performed twin-based heritability and methylation quantitative trait loci (meQTL) analyses for >400,000 DNA methylation sites. We find that the human skin DNA methylome is on average less heritable than previously estimated in blood and other tissues (mean heritability: 10.02%). meQTL analysis identified local genetic effects influencing DNA methylation at 18.8% (76,442) of tested CpG sites, as well as 1,775 CpG sites associated with at least one distal genetic variant. As a functional follow-up, we performed skin expression QTL (eQTL) analyses in a partially overlapping sample of 604 female twins. Colocalization analysis identified over 3,500 shared genetic effects affecting thousands of CpG sites (10,067) and genes (4,475). Mediation analysis of putative colocalized gene-CpG pairs identified 114 genes with evidence for eQTL effects being mediated by DNA methylation in skin, including in genes implicating skin disease such as ALOX12 and CSPG4. We further explored the relevance of skin meQTLs to skin disease and found that skin meQTLs and CpGs under genetic influence were enriched for multiple skin-related genome-wide and epigenome-wide association signals, including for melanoma and psoriasis. Our findings give insights into the regulatory landscape of epigenomic variation in skin.
摘要：
全皮肤DNA甲基化变异与几种疾病有关，包括黑色素瘤,但是其遗传基础尚未完全表征。使用414位健康的英国女性双胞胎的大量皮肤组织样本，我们对>400,000个DNA甲基化位点进行了基于双胞胎的遗传力和甲基化数量性状基因座(meQTL)分析。我们发现，人类皮肤DNA甲基化组的遗传力平均低于先前估计的血液和其他组织（平均遗传力：10.02％）。meQTL分析确定了影响DNA甲基化的18.8％（76,442）测试CpG位点的局部遗传效应，以及与至少一个远端遗传变异相关的1,775个CpG位点。作为一个功能性的后续行动，我们对部分重叠的604对雌性双胞胎进行了皮肤表达QTL(eQTL)分析.共同定位分析确定了超过3,500个共同的遗传效应，影响了数千个CpG位点（10,067个）和基因（4,475个）。推定的共定位基因-CpG对的中介分析鉴定出114个基因，这些基因具有由皮肤中DNA甲基化介导的eQTL效应的证据，包括与皮肤病相关的基因，如ALOX12和CSPG4。我们进一步探索了皮肤meQTL与皮肤病的相关性，发现遗传影响下的皮肤meQTL和CpG富集了多个皮肤相关的全基因组和全基因组关联信号，包括黑色素瘤和牛皮癣.我们的发现为皮肤表观基因组变异的调控景观提供了见解。
