Department of Epidemiology and Health Statistics, School of Public Health, Beijing Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China.
Department of Epidemiology and Health Statistics, School of Public Health, Beijing Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing, China.
Neurobiol Aging. 2021 Jan;97:18-27. doi: 10.1016/j.neurobiolaging.2020.09.019. Epub 2020 Oct 1.
The pathogenesis of Alzheimer's disease (AD) remains largely unclear. Exploring the genetic/epigenetic loci showing pleiotropic association with the neuropathologies of AD may greatly enhance understanding of the mechanisms underlying the development of AD. In this study, using data from the Religious Orders Study and the Rush Memory and Aging Project, we undertook a Mendelian randomization approach integrating genome-wide association studies (GWASs) and DNA methylation quantitative trait locus data to explore pleiotropic epigenetic loci for AD neuropathologies, including amyloid-β (Aβ) load and tau-containing neurofibrillary tangle density. We performed GWASs of DNA methylation in brain tissues from 592 participants and mapped 60,595 cis-SNP-CpG pairs after correction for multiple testing. By linking cis-DNA methylation quantitative trait locus with GWAS results for Aβ load and tau tangles, we identified 47 CpGs showing pleiotropic association with Aβ load by the Mendelian randomization analysis. We then used gene expression data from 537 individuals and performed quantitative trait methylation analysis. We found that 18 of the 47 CpGs were in cis associated with 25 mRNAs/genes, comprising 41 unique CpG-mRNA/gene pairs. Our findings shed light on the role of DNA methylation in the pathogenesis of Aβ.
阿尔茨海默病（AD）的发病机制在很大程度上仍不清楚。探索与 AD 神经病理学具有多效关联的遗传/表观遗传基因座，可能会极大地增进我们对 AD 发病机制的理解。在这项研究中，我们使用宗教秩序研究和拉什记忆与衰老项目的数据，采用整合全基因组关联研究（GWAS）和 DNA 甲基化定量性状基因座数据的孟德尔随机化方法，探索 AD 神经病理学的多效性表观遗传基因座，包括淀粉样蛋白-β（Aβ）负荷和含有 tau 的神经原纤维缠结密度。我们对 592 名参与者的脑组织中的 DNA 甲基化进行了 GWAS，并在进行了多次测试校正后，映射了 60595 个顺式-SNP-CpG 对。通过将顺式 DNA 甲基化定量性状基因座与 Aβ 负荷和 tau 缠结的 GWAS 结果相联系，我们通过孟德尔随机化分析鉴定出 47 个与 Aβ 负荷具有多效关联的 CpG。然后，我们使用来自 537 个人的基因表达数据进行了定量性状甲基化分析。我们发现，在 cis 中，47 个 CpG 中有 18 个与 25 个 mRNA/基因相关，包含 41 个独特的 CpG-mRNA/基因对。我们的研究结果阐明了 DNA 甲基化在 Aβ 发病机制中的作用。
