Epigenetic Profiling of Major Depression

描述(由申请人提供)：精神疾病的病因学，如严重抑郁障碍(MDD)，有遗传、环境和表观遗传学成分。到目前为止，表观遗传成分很少受到关注，但很可能涉及基因组甲基化模式的病理异常，这些模式调控涉及大脑发育或生理的基因。在确定抑郁症的遗传危险因素或环境因素影响抑郁症发展的机制方面进展甚微。对抑郁症表观遗传学特征的研究将导致识别导致疾病状态的表观遗传变异，弥合遗传和环境因素之间的差距。该项目的目标是描述DNA甲基化的表观遗传状态，并确定与MDD病因学相关的新基因和新途径。1.确定MDD中与启动子相关的DNA甲基化变异。我推测，DNA甲基化图谱中的某些遗传表观遗传变异与患抑郁症的风险增加有关。初步研究已经探索了MDD病例和对照组腹侧前额叶皮质全基因组DNA甲基化状态，并确定了200多个差异甲基化的候选基因。从这份清单中，将选择在MDD或中枢神经系统(CNS)功能中具有已知或假设作用的基因，用于在MDD病例和对照的大型小组中进行验证。这项工作将确定与MDD相关的基因相关甲基化变体。2.确定甲基化变异是遗传的还是后天获得的变化。我的工作假设是，通过探测各种组织中甲基化变体的存在，可以区分遗传的甲基化变体和获得性变体。遗传的甲基化变异将在每个组织中保持，而获得性变异将只存在于组织的子集中。3.评价DNA甲基化、基因表达与组蛋白修饰的关系。我假设启动子甲基化水平和基因表达水平之间存在负相关。我预测，在对照组和MDD病例中，不同的组蛋白修饰与甲基化启动子相关。这项工作确定的基因将增加我们对导致抑郁症风险的因素和途径的理解，抑郁症是一种普遍且代价高昂的残疾。这将有助于开发新的治疗靶点，并开发抑郁症风险和治疗反应的诊断方法。

DESCRIPTION (provided by applicant): The etiology of psychiatric disorders such as Major Depressive Disorder (MDD) has genetic, environmental, and epigenetic components. The epigenetic component has received very little attention to date but is likely to involve pathological abnormalities in genomic methylation patterns that regulate genes involved in the development or physiology of the brain. There has been little progress in identifying the inherited risk factors for depression or the mechanisms by which environmental factors influence the development of depression. Study of the epigenetic profile of depression will lead to the identification of epigenetic variants that contribute to the disease state, bridging the gap between the genetic and environmental components. The goal of this project is to profile the epigenetic state of DNA methylation and identify novel genes and pathways involved in the etiology of MDD. 1. Identify promoter-associated DNA methylation variants in MDD. I hypothesize that certain inherited epigenetic variants in DNA methylation profiles are associated with an increased risk of developing depression. Preliminary studies have probed the whole-genome DNA methylation state of the ventral prefrontal cortex in MDD cases and a control and identified over 200 candidate genes with differential methylation. From this list genes with a known or hypothesized role in MDD or central nervous system (CNS) function will be selected for validation in a large panel of MDD cases and controls. This work will identify gene-associated methylation variants correlated with MDD. 2. Determine whether methylation variants are inherited or acquired changes. My working hypothesis is that inherited methylation variants can be distinguished from acquired variants by probing for the existence of the methylation variant in a variety of tissues. Inherited methylation variants will be maintained in every tissue, while acquired variants will only be present in a subset of tissues. 3. Evaluate the relationship between DNA methylation, gene expression and histone modifications. I hypothesize that an inverse correlation exists between promoter methylation levels and gene expression levels. I predict that distinct histone modifications are associated with methylated promoters in controls versus MDD cases. The genes identified by this work will increase our understanding of the factors and pathways that contribute to the risk of depression, a prevalent and costly disability. This will facilitate the development of novel therapeutic targets and the development of diagnostics for depression risk and response to treatment.