Novel regional age-associated DNA methylation changes within human common disease-associated loci

Background: Advancing age progressively impacts on risk and severity of chronic disease. It also modifies the epigenome, with changes in DNA methylation, due to both random drift and variation within specific functional loci. Results: In a discovery set of 2,238 peripheral-blood genome-wide DNA methylomes (MeDIP-seq) aged 19-82 years, we identified 71 age-associated Differentially Methylated Regions (a-DMRs, p < 1.85 x 10-8) within the Linkage Disequilibrium (LD) blocks of the NIH Catalogue of published GWAS SNPs. This included 52 novel regions, 29 within loci not covered by 450k or 27k Illumina array, and with marked enrichment for Poised Promoters and Enhancers across multiple cell types. In a replication set of 2,084 DNA methylomes, 95.7% of the a-DMRs showed the same direction of ageing effect, with 80.3% and 53.3% replicated to p < 0.05 and p < 1.85 x 10-8, respectively. Conclusion: By analysing the functionally enriched disease and trait-associated regions of the human genome, we identified novel epigenetic ageing changes, which could be useful biomarkers or provide mechanistic insights into age-related common diseases.EGA study EGAS00001001910

研究背景：年龄增长会逐步提升慢性病的患病风险并加重其病情严重程度，同时还会因随机漂移与特定功能位点内的变异引发DNA甲基化（DNA methylation）改变，进而修饰表观基因组（epigenome）。
研究结果：在纳入2238份19至82岁受试者外周血全基因组DNA甲基化组的发现队列中，我们采用甲基化DNA免疫沉淀测序（MeDIP-seq）技术，在美国国立卫生研究院（NIH）已发表的全基因组关联研究单核苷酸多态性（GWAS SNPs）目录内的连锁不平衡（Linkage Disequilibrium, LD）区块中，鉴定出71个与年龄相关的差异甲基化区域（age-associated Differentially Methylated Regions, a-DMRs，p < 1.85×10^-8）。其中包含52个全新区域，29个位于450k或27k Illumina芯片（Illumina array）未覆盖的位点中，且在多种细胞类型中均显著富集于 poised启动子（Poised Promoters）与增强子（Enhancers）。在纳入2084份DNA甲基化组的验证队列中，95.7%的a-DMRs表现出与年龄效应一致的调控方向，其中80.3%和53.3%的区域分别达到p < 0.05与p < 1.85×10^-8的验证显著性水平。
研究结论：通过分析人类基因组中功能富集的疾病与性状关联区域，我们鉴定出全新的表观遗传衰老改变，这类改变可作为潜在生物标志物（biomarker），或为年龄相关性常见病的发病机制研究提供机制性见解。本研究为EGA数据库收录研究EGAS00001001910。