情绪和甲基化研究的研究设计和理论基础：双胞胎抑郁症的多组学研究平台

Study Design and Rationale for the Mood and Methylation Study: A Platform for Multi-Omics Investigation of Depression in Twins

Major depression is a complex disorder with no single, direct causal mechanism. Morbidity has been linked to genetic processes, developmental history, and unique environmental exposures. Epigenetic mechanisms, especially DNA methylation, are also likely important factors in the pathogenesis of major depressive disorder (MDD). A community-based twin sample has many advantages for epigenetic studies, given the shared genetic and developmental histories of same-sex twin pairs. This article describes the rationale and study design for the Mood and Methylation Study in which 133 twin pairs (101 monozygotic and 32 dizygotic), both discordant and concordant for lifetime history of MDD, were evaluated on a large number of variables related to MDD. The twins also provided blood samples for an epigenome-wide association study of differentially methylated regions (DMR) relevant to MDD. Although MDD is typically considered a disorder of the central nervous system, it is unfeasible to obtain a large sample of brain tissues. However, epigenetic variation is not limited to the affected tissue but can also be detected in peripheral blood leukocytes. Thus, this study focused on monocytes for the major analyses. Additional plans for the study include gene expression analysis from the same set of twins using RNA-seq and validation of significant DMRs in postmortem brain tissues from a separate sample. Moreover, sufficient samples have been collected to perform future 'multi-omic' analyses, including metabolome, microbiome, and transcriptome. Our long-term goal is to understand how epigenomic and other 'omic' factors can be manipulated for diagnostic, preventive, and therapeutic purposes for MDD and its related conditions. 

严重抑郁症是一种复杂的疾病，没有单一，直接的因果机制。发病率与遗传过程、发育历史和独特的环境暴露有关。表观遗传机制，特别是DNA甲基化，也可能是严重抑郁症（MDD）发病机制的重要因素。基于社区的双胞胎样本对于表观遗传学研究有许多优势，因为同性双胞胎有着共同的遗传和发育历史。本文描述了情绪和甲基化研究的基本原理和研究设计，其中133对双胞胎(101对单卵双胞胎和32对双卵双胞胎)在重度抑郁症（MDD）的一生中都是不一致和一致的，并对大量与MDD相关的变量进行了评估。这对双胞胎还为与MDD相关的差异甲基化区域（DMR）的表观全基因组关联研究提供了血样。尽管MDD通常被认为是中枢神经系统的一种疾病，但是要获得大量的脑组织样本是不可能的。然而，表观遗传变异不仅限于受影响的组织，而且还可以在外周血白细胞中检测到。因此，本研究主要针对单核细胞进行主要分析。这项研究的其他计划包括使用转录组测序技术对同一组双胞胎进行基因表达分析，并从一个单独的样本中验证死后脑组织中的重要DMRs。此外，已经收集了足够的样本来进行未来的“多组学”分析，包括代谢组、微生物组和转录组。我们的长期目标是了解如何操纵表观基因组学和其他“组学”因子用于MDD及其相关病症的诊断，预防和治疗目的。

2018 Dec 发表于Twin Res Hum Genet（IF1.159）