Identification of Epigenetics Correlates between Brain and Peripheral Tissues

摘要 精神疾病，如重度抑郁症 (MDD) 是一种复杂的疾病， 压力源通过表观遗传变化（例如 DNA 甲基化 (DNAm)）增加其发生的可能性。 目前，MDD 疾病相关的 DNAm 模式尚未完全阐明。这部分是由于 依赖于外周组织，例如血液、口腔细胞和唾液，其中 DNAm 如何变化是未知的 这些组织的数据可能准确反映了大脑中的这些变化。因此，有一个紧急的 需要提供一个全面的数据库来交叉比较大脑和大脑之间的 DNAm 模式 其他外周组织，以突出显示可以观察到疾病相关 DNAm 的候选区域。至 为此，我们的总体目标是建立一个全面的表观基因组数据库，其中 DNAm 模式可以 关键大脑区域（例如海马体、杏仁核和背外侧前额叶）之间的交叉比较 皮层）、其神经元和神经胶质成分以及外周组织。我们的中心假设是疾病—— 相关的 DNAm 更可能存在于不同组织之间 DNAm 不同的区域。我们的具体 目标将解决以下问题：在目标 1 中，DNAm 将在全基因组水平和跨基因组水平上进行评估 比较大脑和周围组织，以确定组织之间具有不同 DNAm 的区域。 在目标 2 中，我们将把神经元和神经胶质细胞中的 DNAm 评估扩展到上述关键大脑区域 参与 MDD 并与周围组织进行比较。在目标 3 中，与疾病相关的 DNAm 区域将被 使用来自 206 个 MDD 病例和 206 个匹配对照的病理存档脑组织进行评估。这是 最大的 MDD 尸检研究，专门评估 DNAm。与疾病相关的 DNAm 将是 与组织特异性 DNAm 重叠，以确定 MDD 相关 DNAm 模式可能出现的区域 发生。这项拟议的研究意义重大，因为它将提供一个全面的表观遗传数据库来指导 研究人员对候选区域和合适的外周组织进行 MDD 中 DNAm 变化的研究。它的用途 也可以扩展到其他精神疾病。这项拟议的研究具有创新性，因为它使用了新鲜的大脑， 来自同一个体的神经元、胶质细胞和外周组织建立表观基因组数据库。它还使用 从一大群死后MDD大脑中鉴定出与疾病相关的DNAm，以识别与疾病相关的区域 疾病相关甲基化变化的“热点”。

Abstract Psychiatric disorders such as major depressive disorder (MDD) are complex diseases where negative stressors increase the likelihood of its onset through epigenetic changes, such as DNA methylation (DNAm). Presently, disease-associated DNAm patterns of MDD have not been fully elucidated. This is in part due to the reliance of peripheral tissues such as blood, buccal cells, and saliva where it is unknown how DNAm changes from these tissues might be an accurate reflection of those changes in the brain. As such, there is an urgent need to provide a comprehensive database that would cross-compare DNAm patterns between the brain and other peripheral tissues to highlight candidate regions where disease-associated DNAm can be observed. To this end, our overall goal is to establish a comprehensive epigenomic database where DNAm patterns can be cross-compared between key brain regions (e.g., the hippocampus, amygdala, and dorsolateral prefrontal cortex), their neurons and glia components, and peripheral tissues. Our central hypothesis is that disease- associated DNAm will more likely reside in regions that vary in DNAm between different tissues. Our specific aims will address the following questions: In Aim 1, DNAm will be evaluated at a genome-wide level and cross- compared between brain and peripheral tissues to identify regions which have varying DNAm between tissues. In Aim 2, we will expand DNAm assessment in neuron and glia to the aforementioned key brain regions involved in MDD and compare that with peripheral tissues. In Aim 3, disease-associated DNAm regions will be evaluated using pathology-archived brain tissues from 206 MDD cases and 206 matched controls. This is the largest post-mortem study of MDD that specifically evaluates DNAm. Disease-associated DNAm will be overlaid with tissue-specific DNAm to determine regions where MDD-associated DNAm patterns will likely to occur. This proposed study is significant as it will provide a comprehensive epigenetic database that will guide researchers to candidate regions and suitable peripheral tissues to investigate DNAm changes in MDD. Its use may also be extended to other psychiatric disorders. This proposed study is innovative as it uses fresh brain, neuron, glia and peripheral tissues from the same individual to establish an epigenome database. It also uses disease-associated DNAm identified from a large cohort of post-mortem MDD brains to identify regions that are “hot-spots” for disease-associated methylation changes.