Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA.
Am J Hum Genet. 2010 Mar 12;86(3):411-9. doi: 10.1016/j.ajhg.2010.02.005.
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.
我们观察到 153 个人类成年小脑样本中 6229 个基因的 8590 个 CpG 位点的 DNA 甲基化存在广泛的个体间差异，这些差异富集在 CpG 岛“岸”区以及离 CpG 岛更远的位置。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），以寻找甲基化数量性状基因座（mQTL）。顺式关联是指 CpG 位点附近 SNP 与甲基化的相关性。736 个 CpG 位点与 2878 个 SNP 表现出全基因组显著的顺式关联（经过所有测试标记和甲基化表型的置换校正后）。在对甲基化的转座分析中，检测到远距离调节效应的关联，在全表型校正后，12 个 CpG 位点和 38 个 SNP 的关联仍然显著。为了研究 mQTL 的功能效应，我们分析了 85 个与我们观察到的遗传调控甲基化相关的基因，并且我们有这些基因的高质量基因表达数据。有 10 个基因表现出 SNP-甲基化-表达的三向关联，即同一个 SNP 同时与 DNA 甲基化和基因表达显著相关，而 DNA 甲基化与基因表达显著相关。因此，我们证明了 DNA 甲基化在人类大脑中是一种经常遗传的、连续的、定量的可变性特征。与等位基因特异性甲基化不同，遗传多态性标记了与其 CpG 位点在可测量距离内的顺式和反式调节遗传位点。一些遗传调控的 DNA 甲基化与遗传调控的基因表达变异直接相关。
