阿尔茨海默病的全基因组表观遗传关联研究复制了 22 个差异甲基化位置和 30 个差异甲基化区域。
Epigenome-wide association study of Alzheimer's disease replicates 22 differentially methylated positions and 30 differentially methylated regions.
机构信息
Neuroscience, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA.
Discovery Science, Janssen Research & Development, LLC, Spring House, PA, USA.
出版信息
Clin Epigenetics. 2020 Oct 17;12(1):149. doi: 10.1186/s13148-020-00944-z.
BACKGROUND
Growing evidence shows that epigenetic modifications play a role in Alzheimer's disease (AD). We performed an epigenome-wide association study (EWAS) to evaluate the DNA methylation differences using postmortem superior temporal gyrus (STG) and inferior frontal gyrus (IFG) samples.
RESULTS
Samples from 72 AD patients and 62 age-matched cognitively normal controls were assayed using Illumina Infinium MethylationEPIC BeadChip. Five and 14 differentially methylated positions (DMPs) associated with pathology (i.e., Braak stage) with p value less than Bonferroni correction threshold of 6.79 × 10 in the STG and IFG were identified, respectively. These cytosine-phosphate-guanine (CpG) sites included promoter associated cg26263477 annotated to ABCA7 in the STG (p = 1.21 × 10), and cg14058329 annotated to the HOXA5/HOXA3/HOXA-AS3 gene cluster (p = 1.62 × 10) and cg09448088 (p = 3.95 × 10) annotated to MCF2L in the IFG. These genes were previously reported to harbor DMPs and/or differentially methylated regions (DMRs). Previously reported DMPs annotated to RMGA, GNG7, HOXA3, GPR56, SPG7, PCNT, RP11-961A15.1, MCF2L, RHBDF2, ANK1, PCNT, TPRG1, and RASGEF1C were replicated (p < 0.0001). One hundred twenty-one and 173 DMRs associated with pathology in the STG and IFG, respectively, were additionally identified. Of these, DMRs annotated to 30 unique genes were also identified as significant DMRs in the same brain region in a recent meta-analysis, while additional DMRs annotated to 12 genes were reported as DMRs in a different brain region or in a cross-cortex meta-analysis. The significant DMRs were enriched in promoters, CpG islands, and exons in the genome. Gene set enrichment analysis of DMPs and DMRs showed that gene sets involved in neuroinflammation (e.g., microglia differentiation), neurogenesis, and cognition were enriched (false discovery rate (FDR) < 0.05).
CONCLUSIONS
Twenty-two DMPs and 30 DMRs associated with pathology were replicated, and novel DMPs and DMRs were discovered.
背景
越来越多的证据表明，表观遗传修饰在阿尔茨海默病（AD）中起作用。我们进行了全基因组关联研究（EWAS），以评估使用死后颞上回（STG）和额下回（IFG）样本的 DNA 甲基化差异。
结果
对 72 名 AD 患者和 62 名年龄匹配的认知正常对照者的样本进行了 Illumina Infinium MethylationEPIC BeadChip 检测。在 STG 和 IFG 中，分别鉴定出了与病理学（即 Braak 分期）相关的 5 个和 14 个差异甲基化位置（DMP），其 p 值小于 Bonferroni 校正阈值 6.79×10-8。这些胞嘧啶-磷酸-鸟嘌呤（CpG）位点包括与 ABCA7 相关的 STG 中的 cg26263477（p=1.21×10-8），以及 cg14058329 注释到 HOXA5/HOXA3/HOXA-AS3 基因簇（p=1.62×10-8）和 cg09448088（p=3.95×10-8）注释到 IFG 中的 MCF2L。这些基因之前被报道含有 DMPs 和/或差异甲基化区域（DMRs）。先前报道的注释到 RMGA、GNG7、HOXA3、GPR56、SPG7、PCNT、RP11-961A15.1、MCF2L、RHBDF2、ANK1、PCNT、TPRG1 和 RASGEF1C 的 DMPs 得到了复制（p<0.0001）。在 STG 和 IFG 中，分别另外鉴定出了与病理学相关的 121 个和 173 个 DMRs。其中，在最近的一项荟萃分析中，还鉴定出了与同一脑区的 30 个独特基因相关的 DMRs，而在不同脑区或跨皮质荟萃分析中报道的另外 12 个基因的 DMRs。显著的 DMRs在基因组中富含启动子、CpG 岛和外显子。DMPs 和 DMRs 的基因集富集分析表明，神经炎症（如小胶质细胞分化）、神经发生和认知相关的基因集被富集（错误发现率（FDR）<0.05）。
结论
复制了与病理学相关的 22 个 DMPs 和 30 个 DMRs，并发现了新的 DMPs 和 DMRs。
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