Genetic Control of Individual Differences in Gene-Specific Methylation in Human Brain
Genetic Control of Individual Differences in Gene-Specific Methylation in Human Brain
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DOI：
10.1016/j.ajhg.2010.02.005
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发表时间：
2010-03-12
影响因子：
9.8
通讯作者：
Liu, Chunyu
中科院分区：
文献类型：
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作者：
Zhang, Dandan;Cheng, Lijun;Liu, Chunyu
我们已经观察到广泛的个体间差异的DNA甲基化的8590个CpG位点的6229个基因在153人成人小脑样本，丰富的CpG岛的“海岸”，并在进一步的距离CpG岛。为了寻找调节这种变异的遗传因素，我们对8590个可检测的CpG位点进行了全基因组关联研究（GWAS）甲基化数量性状位点（mQTL）定位。顺式关联是指甲基化与CpG位点的1 Mb内的SNP的相关性。736个CpG位点与2878个SNP表现出表型范围内的显著顺式关联（在对所有测试的标志物和甲基化表型进行排列校正后）。在测试远端调节效应的甲基化反式分析中，在全表型校正后，12个CpG位点和38个SNP的关联仍然显着。为了研究mQTL的功能效应，我们分析了85个基因，这些基因具有我们观察到的遗传调控甲基化，并且我们有高质量的基因表达数据。10个基因表现出SNP-甲基化-表达的三向关联，同一SNP同时表现出与DNA甲基化和基因表达的显著关联，而DNA甲基化与基因表达显著相关。因此，我们证明了DNA甲基化在人脑中经常是一种可遗传的连续定量变量性状。与等位基因特异性甲基化不同，遗传多态性标记顺式和反式调节基因位点，其距离CpG位点可测量。一些基因调控的DNA甲基化与基因表达变异直接相关。
We have observed extensive interindividual differences in DNA methylation of 8590 CpG sites of 6229 genes in 153 human adult cerebellum samples, enriched in CpG island "shores" and at further distances from CpG islands. To search for genetic factors that regulate this variation, we performed a genome-wide association study (GWAS) mapping of methylation quantitative trait loci (mQTLs) for the 8590 testable CpG sites. cis association refers to correlation of methylation with SNPs within 1 Mb of a CpG site. 736 CpG sites showed phenotype-wide significant cis association with 2878 SNPs (after permutation correction for all tested markers and methylation phenotypes). In trans analysis of methylation, which tests for distant regulation effects, associations of 12 CpG sites and 38 SNPs remained significant after phenotype-wide correction. To examine the functional effects of mQTLs, we analyzed 85 genes that were with genetically regulated methylation we observed and for which we had quality gene expression data. Ten genes showed SNP-methylation-expression three-way associations-the same SNP simultaneously showed significant association with both DNA methylation and gene expression, while DNA methylation was significantly correlated with gene expression. Thus, we demonstrated that DNA methylation is frequently a heritable continuous quantitatively variable trait in human brain. Unlike allele-specific methylation, genetic polymorphisms mark both cis- and trans-regulatory genetic sites at measurable distances from their CpG sites. Some of the genetically regulated DNA methylation is directly connected with genetically regulated gene expression variation.