Identification of Epigenetics Correlates between Brain and Peripheral Tissues

摘要 精神障碍，如重度抑郁症（MDD）是一种复杂的疾病， 应激源通过表观遗传变化（如DNA甲基化（DNAm））增加其发作的可能性。 目前，MDD的疾病相关DNA模式尚未完全阐明。这部分是由于 依赖外周组织，如血液、口腔细胞和唾液，其中DNA m如何变化是未知的 可能是大脑变化的准确反映。因此，有一个紧迫的 需要提供一个全面的数据库，将交叉比较大脑和大脑之间的DNA模式， 其他外周组织，以突出可以观察到疾病相关DNAm的候选区域。到 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 在关键脑区域之间进行交叉比较（例如，海马体杏仁核和背外侧前额叶 皮质）、它们的神经元和神经胶质成分以及外周组织。我们的核心假设是疾病- 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 目的将解决以下问题：在目的1中，DNAm将在全基因组水平和跨基因组水平上进行评估。 比较脑和外周组织之间的差异，以识别组织之间具有不同DNAm的区域。 在目标2中，我们将神经元和神经胶质细胞中的DNAm评估扩展到上述关键脑区域 并与周围组织进行比较。在目标3中，疾病相关的DNAm区域将被 使用来自206例MDD病例和206例匹配对照的病理学存档脑组织进行评估。这是 专门评估DNA的MDD最大的尸检研究。疾病相关DNA m将 与组织特异性DNAm重叠，以确定MDD相关DNAm模式可能 发生.这项拟议的研究是重要的，因为它将提供一个全面的表观遗传数据库，将指导 研究人员将候选区域和合适的外周组织用于研究MDD中的DNAm变化。其使用 也可以扩展到其他精神疾病。这项研究是创新的，因为它使用了新鲜的大脑， 神经元、神经胶质和外周组织，以建立表观基因组数据库。它还使用 从一个大的死亡后MDD大脑队列中鉴定出的疾病相关DNA， 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.