Epigenetic Determinants of Major Depression: a Monozygotic Discordant Twin Study

描述（由申请人提供）：重度抑郁症（MDD）是一种毁灭性的精神疾病，影响着数百万美国人。尽管进行了大量的研究，但还没有确定具体的风险因素在重度抑郁症中起因果作用。表观遗传修饰，特别是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使人衰弱的疾病进行早期诊断、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。我们的中心假设是异常的DNA甲基化和基因表达的改变与重度抑郁症有关。提出这项研究的基本原理是：一旦我们知道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靶点，用于风险评估、预防和治疗重度抑郁症和相关精神疾病。我们提出了三个具体目标：(1)确定与MDD相关的差异甲基化区域（DMRs）。本研究的目的是进行表观基因组范围内的DNA甲基化分析，以确定来自华盛顿大学双胞胎登记处（UWTR）的100对单卵（MZ）不一致双胞胎的单核细胞DNA中导致MDD的表观遗传变异。UWTR是美国一个大型社区双胞胎登记处。(2)在两个独立样本中复制aim 1中排名前50位的基因。包括从同一登记处招募的80对MZ不一致的双胞胎，以及36名具有良好特征的重度抑郁症患者的死后脑组织和匹配的对照组。(3)通过分析四个大脑区域（额叶皮质、海马体、杏仁核和扣带皮质）的基因表达水平，确定血液和大脑中阳性甲基化发现的功能重要性。将鉴定与MDD相关的差异表达基因。将进行综合分析，以阐明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。该研究是同类研究中唯一一个在匹配良好的MZ不一致双胞胎样本中确定MDD的功能性表观遗传决定因素的研究，随后在死后脑组织（MDD的受影响器官）中进行复制。由于具有差异甲基化和差异表达的基因极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，并从根本上推动精神病学遗传学领域的发展，因此本研究预计将产生重要的积极影响。

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.