口腔细胞中 DNA 甲基化的全基因组分析：对同卵双胞胎和 mQTLs 的研究。
Genome-wide analysis of DNA methylation in buccal cells: a study of monozygotic twins and mQTLs.
机构信息
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Van Der Boechorststraat 1, 1081BT, Amsterdam, The Netherlands.
Avera Institute for Human Genetics, 3720 W. 69th Street, Sioux Falls, SD, 57108, USA.
出版信息
Epigenetics Chromatin. 2018 Sep 25;11(1):54. doi: 10.1186/s13072-018-0225-x.
BACKGROUND
DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA.
RESULTS
Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3.
CONCLUSIONS
We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.
背景
DNA 甲基化阵列被广泛应用于表观基因组全基因组关联研究和甲基化数量性状基因座（mQTL）研究。在这里，我们首次对同卵（MZ）双胞胎的相关性和使用 Illumina MethylationEPIC BeadChip（EPIC 阵列）获得的 mQTL 进行了全基因组分析，并比较了 EPIC 阵列与 Illumina HumanMethylation450 BeadChip（HM450 阵列）在口腔衍生 DNA 方面的性能。
结果
对来自 49 对 MZ 双胞胎的 102 个口腔衍生 DNA 样本获得了高质量的 EPIC 数据（平均年龄为 7.5 岁，范围为 1-10 岁）。口腔拭子中细胞含量的 MZ 双胞胎差异是导致其 DNA 甲基化谱差异的主要驱动因素，这突出了在口腔衍生 DNA 的 DNA 甲基化研究中调整细胞组成的重要性。在调整细胞组成后，EPIC 阵列中 MZ 双胞胎的全基因组平均相关性（r）为 0.21，在 84 对双胞胎中进行的顺式 mQTL 分析确定了 1,296,323 个显著关联（FDR 5%），包含 33,749 个甲基化位点和 616,029 个遗传变异。与 HM450 上存在的探针（N=406,822，平均 r=0.20）相比，新型 EPIC 探针（N=383,066，平均 r=0.22）的 MZ 双胞胎相关性略大（p<2.2×10）。与 mQTL 相关的新型 EPIC 探针的比例也大于与 mQTL 相关的 HM450 探针（新型 EPIC 探针有显著 mQTL 的比例为 4.7%，HM450 探针有 mQTL 的比例为 3.9%，p<2.2×10）。与 mQTL 相关的 MZ 相关性较大的甲基化位点和与 mQTL 相关的位点在上皮细胞 DNA 酶 I 超敏位点（DHS）、增强子和组蛋白标记 H3K4me3 中富集最多。
结论
我们的结论是，家族因素对 DNA 甲基化个体差异的贡献以及 mQTL 的影响在新型 EPIC 探针中更大，特别是那些位于与研究组织特定活性区域相关的调控元件内的探针。
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