Epigenetic Determinants of Major Depression: a Monozygotic Discordant Twin Study

描述(申请人提供)：严重抑郁障碍(MDD)是一种毁灭性的精神障碍，影响数百万美国人。尽管进行了大量研究，但尚未确定具体的危险因素在MDD中起因果作用。表观遗传修饰，尤其是DNA甲基化，越来越被认为是抑郁症发病的关键机制。然而，将异常甲基化与抑郁症联系起来的生物学途径仍然知之甚少。这种不确定性极大地阻碍了我们对这种衰弱疾病进行早期诊断、预防和治疗的能力。本研究的目的是确定MDD的功能性表观遗传决定因素。我们的中心假设是DNA甲基化异常和由此导致的基因表达变化与MDD有关。这项拟议研究的基本原理是：一旦我们了解了抑郁症的表观遗传决定因素，我们将能够开发新的表观遗传标记和治疗目标，用于MDD和相关精神疾病的风险评估、预防和治疗。我们提出了三个具体目标：(1)识别与MDD相关的差异甲基化区域(DMR)。其目的是进行表观基因组范围的DNA甲基化分析，以确定导致MDD的单核细胞DNA的表观遗传变异，这些变异来自华盛顿大学双胞胎登记处(UWTR)的100对单卵(MZ)不协调双胞胎。(2)在两个独立样本中复制AIM 1中排名最高的50个基因，包括从同一登记处招募的80对MZ不协调双胞胎，以及36例特征良好的MDD患者和匹配对照的死后脑组织。(3)通过分析四个脑区(额叶皮质、海马体、杏仁核和扣带回)的基因表达水平，确定血液和脑中甲基化阳性结果的功能重要性。与MDD相关的差异表达基因将被鉴定出来。综合分析将被用来阐明DNA甲基化模式和与MDD相关的同源基因的基因表达之间的联系。这项拟议的研究是唯一一项在匹配良好的MZ不协调双胞胎样本中确定MDD的功能性表观遗传决定因素的研究，然后在MDD的受累器官死后脑组织中复制。这里提出的工作有望产生重要的积极影响，因为具有差异甲基化和表达的基因除了从根本上促进精神遗传学领域的发展外，很有可能为抑郁症及其相关精神疾病的预防、干预和治疗提供新的表观遗传学靶点。

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a devastating psychiatric disorder that affects millions of Americans. Despite substantial research, no specific risk factor has yet been identified as having a causal role in MDD. Epigenetic modifications, especially DNA methylation, are increasingly being recognized as a key mechanism involved in the pathogenesis of depression. However, the biological pathways linking aberrant methylation to depression remain poorly understood. This uncertainty greatly hampers our ability to implement early diagnosis, prevention and treatment for this debilitating disorder. The objective of this study is to identify functional epigenetic determinants for MDD. Our central hypothesis is that aberrant DNA methylation and resulting alterations in gene expression are associated with MDD. The rationale for the proposed research is that: once we know the epigenetic determinants for depression, we will be able to develop novel epigenetic markers and therapeutic targets for risk assessment, prevention and treatment of MDD and related psychiatric conditions. We proposed three specific aims: (1) Identify differentially methylated regions (DMRs) associated with MDD. This aim is to conduct an epigenome-wide DNA methylation analysis to identify epigenetic variations contributing to MDD in monocytes DNA from 100 monozygotic (MZ) discordant twin pairs from the University of Washington Twin Registry (UWTR), a large community-based twin registry in the U.S. (2) Replicate the top 50 ranked genes from Aim 1 in two independent samples, including 80 MZ discordant twin pairs recruited from the same registry and 36 postmortem brain tissue of well-characterized MDD patients and matched controls. (3) Determine the functional importance of the positive methylation findings in both blood and brain by profiling gene expression levels in each of the four brain regions (frontal cortex, hippocampus, amygdala, and cingulate cortex). Differential expressed genes related to MDD will be identified. Integrative analyses will be performed to elucidate the connections between DNA methylation patterns and gene expression of cognate genes in relation to MDD. The proposed study is the only one of its kind to identify functional epigenetic determinants for MDD in a well- matched MZ discordant twin sample, followed by replication in postmortem brain tissue, the affected organ in MDD. The work proposed here is expected to have an important positive impact, because genes with both differential methylation and expression are highly likely to provide novel epigenetic targets for prevention, intervention and treatment for depression and its related psychiatric conditions in addition to fundamentally advancing the fields of psychiatric genetics.