De Jager Philip L, Srivastava Gyan, Lunnon Katie, Burgess Jeremy, Schalkwyk Leonard C, Yu Lei, Eaton Matthew L, Keenan Brendan T, Ernst Jason, McCabe Cristin, Tang Anna, Raj Towfique, Replogle Joseph, Brodeur Wendy, Gabriel Stacey, Chai High S, Younkin Curtis, Younkin Steven G, Zou Fanggeng, Szyf Moshe, Epstein Charles B, Schneider Julie A, Bernstein Bradley E, Meissner Alex, Ertekin-Taner Nilufer, Chibnik Lori B, Kellis Manolis, Mill Jonathan, Bennett David A
1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
Nat Neurosci. 2014 Sep;17(9):1156-63. doi: 10.1038/nn.3786. Epub 2014 Aug 17.
We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.
我们使用了一组708例前瞻性收集的经尸检的大脑来评估与阿尔茨海默病（AD）相关的大脑DNA甲基化状态。我们发现，在415,848个被检测的CpG位点中的71个位点的甲基化水平与AD病理负担显著相关，包括ABCA7和BIN1区域中的CpG位点，这些区域含有已知的AD易感变体。我们在一组独立的117名受试者中验证了11个差异甲基化区域。此外，我们对这些CpG关联进行了功能验证，并确定了其RNA表达在AD中发生改变的附近基因：ANK1、CDH23、DIP2A、RHBDF2、RPL13、SERPINF1和SERPINF2。我们的分析表明，鉴于我们在症状前受试者中观察到了这些DNA甲基化变化，并且六个经验证的基因与已知的AD易感基因网络相关，这些DNA甲基化变化可能在AD的发病中起作用。
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