Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements
Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements
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DOI：
10.1016/j.ajhg.2013.10.004
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发表时间：
2013-11-07
影响因子：
9.8
通讯作者：
Deloukas, Panos
中科院分区：
文献类型：
--
作者：
Grundberg, Elin;Meduri, Eshwar;Deloukas, Panos
表观遗传修饰，如DNA甲基化，在基因调控和疾病易感性中起着关键作用。然而，关于甲基化变异在全基因组范围内的频率、定位和功能，以及它如何受到遗传和环境因素的调节，人们知之甚少。我们利用多组织人类表达资源(MuTHER)，从648对双胞胎中产生了Illumina 450K脂肪甲基组数据。我们发现单个CPGS的变异度很低，并且在启动子中变异性被抑制。我们注意到DNA甲基化变异是高度遗传的(h(中位数)(2)=0.34)，共同的环境效应与代谢表型相关的CPGS相关。对甲基化数量性状基因座(MetQTL)的分析表明，28%的CPGS与邻近的SNPs相关，当它们与来自同一个体的脂肪表达数量性状基因座(EQTL)重叠时，我们发现6%的基因座同时起到调控基因表达和DNA甲基化的作用。这些关联是双向的，但与启动子CPGS存在明显的负关联。MetQTL与脂肪参考表观基因组和疾病关联的整合显示，MetQTL重叠的代谢性状或疾病基因在增强子中显著丰富(对高密度脂蛋白胆固醇和体重指数[BMI]影响最大)。我们跟踪了BMI SNP rs713586，这是一个cg01884057元QTL，与ADCY3上游的增强子重叠，并使用亚硫酸氢盐测序来精炼该区域。我们的结果表明，广泛的群体不变性仍然依赖于脂肪DNA甲基化的序列，但纳入调控元件的图谱有助于以组织依赖的方式将CpG变异与基因调控和疾病风险联系起来。
Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(median)(2) = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.