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.

中文翻译：

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对健康老年双胞胎皮肤甲基化组的遗传影响


全皮肤 DNA 甲基化变异与包括黑色素瘤在内的多种疾病有关，但其遗传基础尚未完全表征。使用来自 414 名健康女性英国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位点 （meQTL） 分析。我们发现，人类皮肤 DNA 甲基化组在血液和其他组织中的遗传性平均低于先前估计的 （平均遗传力： 10.02%）。meQTL 分析确定了影响 DNA 甲基化的局部遗传效应，在 18.8% （76,442） 的测试中 CpG 位点，以及与至少一个远端遗传变异相关的 1,775 个 CpG 位点。作为功能随访，我们在 604 名女性双胞胎的部分重叠样本中进行了皮肤表达 QTL （eQTL） 分析。共定位分析确定了 3,500 多个共同的遗传效应，影响了数千个 CpG 位点 （10,067） 和基因 （4,475）。推定的共定位基因-CpG 对的介导分析确定了 114 个基因，并有证据表明 eQTL 效应是由皮肤中的 DNA 甲基化介导的，包括与皮肤病有关的基因，如 ALOX12 和 CSPG4。我们进一步探讨了皮肤 meQTLs 与皮肤病的相关性，发现受遗传影响的皮肤 meQTLs 和 CpGs 富含多种皮肤相关的全基因组和表观基因组范围关联信号，包括黑色素瘤和银屑病。我们的研究结果让我们深入了解了皮肤表观基因组变异的调节格局。