Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
Transl Psychiatry. 2019 Jan 29;9(1):39. doi: 10.1038/s41398-019-0372-2.
A consistent gene set undergoes age-associated expression changes in the human cerebral cortex, and our Age-by-Disease Model posits that these changes contribute to psychiatric diseases by "pushing" the expression of disease-associated genes in disease-promoting directions. DNA methylation (DNAm) is an attractive candidate mechanism for age-associated gene expression changes. We used the Illumina HumanMethylation450 array to characterize genome-wide DNAm in the postmortem orbital frontal cortex from 20 younger (<42 years) and 19 older (>60 years) subjects. DNAm data were integrated with existing normal brain aging expression data and sets of psychiatric disease risk genes to test the hypothesis that age-associated DNAm changes contribute to age-associated gene expression changes and, by extension, susceptibility to psychiatric diseases. We found that age-associated differentially methylated regions (aDMRs) are common, robust, bidirectional, concentrated in CpG island shelves and sea, depleted in CpG islands, and enriched among genes undergoing age-associated expression changes (OR = 2.30, p = 1.69 × 10). We found the aDMRs are enriched among genetic association-based risk genes for schizophrenia, Alzheimer's disease (AD), and major depressive disorder (MDD) (OR = 2.51, p = 0.00015; OR = 2.38, p = 0.036; and OR = 3.08, p = 0.018, respectively) as well as expression-based MDD-associated genes (OR = 1.48, p = 0.00012). Similar patterns of enrichment were found for aDMRs that correlate with local gene expression. These results were replicated in a large publically-available dataset, and confirmed by meta-analysis of the two datasets. Our findings suggest DNAm is a molecular mechanism for age-associated gene expression changes and support a role for DNAm in age-by-disease interactions through preferential targeting of disease-associated genes.
一个一致的基因集在人类大脑皮层中经历与年龄相关的表达变化，我们的年龄与疾病模型假设这些变化通过“推动”疾病相关基因在促进疾病的方向上的表达，从而导致精神疾病。DNA 甲基化（DNAm）是与年龄相关的基因表达变化的一个有吸引力的候选机制。我们使用 Illumina HumanMethylation450 阵列来描述 20 名较年轻（<42 岁）和 19 名较年长（>60 岁）受试者死后眶额皮质的全基因组 DNAm。将 DNAm 数据与现有的正常大脑老化表达数据和精神疾病风险基因集进行整合，以测试以下假设：与年龄相关的 DNAm 变化有助于与年龄相关的基因表达变化，并且，通过扩展，易患精神疾病。我们发现，与年龄相关的差异甲基化区域（aDMRs）是常见的、稳健的、双向的，集中在 CpG 岛架和海，在 CpG 岛中耗尽，并且在与年龄相关的表达变化的基因中富集（OR=2.30，p=1.69×10）。我们发现，aDMRs 在精神分裂症、阿尔茨海默病（AD）和重度抑郁症（MDD）的基于遗传关联的风险基因中富集（OR=2.51，p=0.00015；OR=2.38，p=0.036；OR=3.08，p=0.018，分别）以及基于表达的 MDD 相关基因（OR=1.48，p=0.00012）。与局部基因表达相关的 aDMR 也存在类似的富集模式。这些发现结果在一个大型的公共可用数据集上得到了复制，并通过对两个数据集的荟萃分析得到了验证。我们的研究结果表明，DNAm 是与年龄相关的基因表达变化的分子机制，并支持 DNAm 在年龄与疾病相互作用中通过优先靶向疾病相关基因的作用。
