Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 N Wolfe St, Suite 300, Baltimore, MD, 21205, USA.
Center for Computational Biology, Johns Hopkins University, Baltimore, MD, 21205, USA.
Acta Neuropathol. 2019 Apr;137(4):557-569. doi: 10.1007/s00401-019-01966-5. Epub 2019 Feb 2.
Late-onset Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD, we surveyed 420,852 DNA methylation (DNAm) sites from neurotypical controls (N = 49) and late-onset AD patients (N = 24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum). We identified 858 sites with robust differential methylation collectively annotated to 772 possible genes (FDR < 5%, within 10 kb). These sites were overrepresented in AD genetic risk loci (p = 0.00655) and were enriched for changes during normal aging (p < 2.2 × 10), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR < 5%). To functionally validate these associations, we generated and analyzed corresponding transcriptome data to prioritize 130 genes within 10 kb of the differentially methylated sites. These 130 genes were differentially expressed between AD cases and controls and their expression was associated with nearby DNAm (p < 0.05). This integrated analysis implicates novel genes in Alzheimer's disease, such as ANKRD30B. These results highlight DNAm differences in Alzheimer's disease that have gene expression correlates, further implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.
迟发性阿尔茨海默病（AD）是一种复杂的与年龄相关的神经退行性疾病，可能涉及表观遗传因素。为了更好地了解与 AD 相关的表观遗传状态，我们调查了来自 49 名神经典型对照者（N=49）和 24 名迟发性 AD 患者（N=24）的 420852 个 DNA 甲基化（DNAm）位点，这些位点分布在四个大脑区域（海马体、内嗅皮层、背外侧前额叶皮层和小脑）。我们确定了 858 个具有稳健差异甲基化的位点，这些位点共同注释到 772 个可能的基因（FDR<5%，在 10kb 内）。这些位点在 AD 遗传风险基因座中过表达（p=0.00655），并且在正常衰老过程中富集（p<2.2×10），附近的基因富集与细胞黏附、免疫和钙稳态相关的过程（FDR<5%）。为了对这些关联进行功能验证，我们生成并分析了相应的转录组数据，以优先考虑 130 个位于差异甲基化位点 10kb 内的基因。这 130 个基因在 AD 病例和对照组之间的表达存在差异，并且它们的表达与附近的 DNAm 相关（p<0.05）。这项综合分析表明，ANKRD30B 等新基因与阿尔茨海默病有关。这些结果突出了阿尔茨海默病中的 DNAm 差异，这些差异与基因表达相关，进一步表明 DNAm 是与 AD 相关的病理性分子变化的潜在表观遗传机制。此外，我们的框架说明了整合表观遗传和转录组数据来理解复杂疾病的价值。
