Psychosis-associated DNA methylomic variation in Alzheimer's disease cortex.
Psychosis-associated DNA methylomic variation in Alzheimer's disease cortex.
复制标题
阿尔茨海默病皮质中与精神病相关的 DNA 甲基化变异。
DOI：
10.1016/j.neurobiolaging.2020.01.001
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发表时间：
2020
影响因子：
4.2
通讯作者：
Pishva E
中科院分区：
文献类型：
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作者：
Pishva E
精神症状是阿尔茨海默病（AD）的常见和衰弱特征，并与更快速的衰退过程相关。目前来自死后和神经影像学研究的证据表明，额叶、颞叶和顶叶有单胺能通路中断的报道。然而，这背后的分子机制尚不清楚。在本研究中，我们研究了29名患有精神病的AD供者和18名没有精神病的AD供者的死后脑样本中与AD精神病相关的3个关键脑区域（前额皮质、内嗅皮质和颞上回）的甲基化变异。我们在许多基因座中发现了与精神分裂症相关的甲基组变化，这些基因在已知的与精神分裂症相关的遗传和表观遗传变异中富集。其中一个已知的基因座位于as3mt基因中，该基因先前在一项大型GWAS荟萃分析中与精神分裂症有关。我们使用亚硫酸氢盐焦磷酸测序来确认asm3tgene中4个相邻CpG位点的低甲基化。最后，我们的区域分析提名了多个CpG位点intbx15和wt1，这是先前与AD有关的基因。因此，我们研究的一个潜在含义是，精神病相关的变异是否驱动了阿尔茨海默病病例对照研究中报告的关联。
Psychotic symptoms are a common and debilitating feature of Alzheimer's disease (AD) and are associated with a more rapid course of decline. Current evidence from postmortem and neuroimaging studies implicates frontal, temporal, and parietal lobes, with reported disruptions in monoaminergic pathways. However, the molecular mechanisms underlying this remain unclear. In the present study, we investigated methylomic variation associated with AD psychosis in 3 key brain regions implicated in the etiology of psychosis (prefrontal cortex, entorhinal cortex, and superior temporal gyrus) in postmortem brain samples from 29 AD donors with psychosis and 18 matched AD donors without psychosis. We identified psychosis-associated methylomic changes in a number of loci, with these genes being enriched in known schizophrenia-associated genetic and epigenetic variants. One of these known loci resided in theAS3MTgene—previously implicated in schizophrenia in a large GWAS meta-analysis. We used bisulfite-pyrosequencing to confirm hypomethylation across 4 neighboring CpG sites in theASM3Tgene. Finally, our regional analysis nominated multiple CpG sites inTBX15andWT1, which are genes that have been previously implicated in AD. Thus one potential implication from our study is whether psychosis-associated variation drives reported associations in AD case-control studies.