The Presence of Methylation Quantitative Trait Loci Indicates a Direct Genetic Influence on the Level of DNA Methylation in Adipose Tissue

Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.与CpG位点处DNA甲基化相关的遗传变异——甲基化数量性状位点（methylation quantitative trait loci, meQTLs），为疾病相关单核苷酸多态性（single nucleotide polymorphisms, SNPs）提供了潜在的生物学作用机制。本研究旨在探究腹部皮下脂肪组织（abdominal subcutaneous adipose tissue, SAT）中是否存在meQTLs，以及CpG甲基化是否与代谢综合征（metabolic syndrome, MetSyn）表型存在关联。我们对38名无关个体的腹部SAT样本中的27718个基因组区域开展了差异甲基化杂交（differential methylation hybridization, DMH）分析，同时获取了5227243个SNPs的基因型数据与17209个mRNA转录本的表达水平数据。我们在由181名女性双胞胎组成的独立队列中，对显著meQTLs进行了验证与重复验证实验。在初步研究中，以5%的错误发现率为显著性阈值，我们发现149个DMH区域的甲基化水平与该区域±500千碱基对顺式区域内的至少一个SNP存在显著关联。我们在重复验证实验中对其中19个关联信号进行了验证，结果显示其中5个与初步研究中对应的meQTL SNPs存在显著关联。我们的表达数据分析显示，这149个meQTL的核心SNP均未成为显著的表达数量性状位点（expression quantitative trait locus, eQTL），但我们观察到2个mRNA转录本的表达水平与顺式甲基化状态存在关联。本研究结果表明，腹部SAT中的DNA CpG甲基化在一定程度上受遗传调控。本研究为未来脂肪组织DNA甲基化的相关研究提供了重要的基础起点。