Integrative Genomics of the Corticolimbic Circuit in Major Depressive Disorder

严重抑郁障碍(MDD)是一种经常复发的疾病，是导致 世界各地的残疾和自杀的一个重要风险因素。尽管得到了更好的认可和更多的治疗， MDD的流行率和总体自杀率保持不变。尽管种类繁多， 治疗是可用的，它们的总体疗效仍然不大，只有三分之一的接受治疗的患者表现出完全缓解。 减刑。迫切需要新的治疗方法，然而新型抗抑郁药物的开发已经 由于我们对MDD的病理生理学了解有限。在这项建议中，我们寻求 到目前为止，在死后大脑中进行最大和最全面的MDD分子研究。我们会 利用利伯脑发育研究所的大量尸检脑标本 全面研究与MDD和MDD相关的全基因组表达和表观遗传特征 自杀发生在皮质边缘回路的三个脑区，包括前扣带回皮质(ACC)， 杏仁核和背侧前额叶皮质(DLPFC)。我们建议进行RNA测序， 400例慢性阻塞性肺疾病患者大脑皮质和杏仁核DNA甲基化及染色质可及性分析 并将这些结果与Brainseq项目的DLPFC的研究结果结合起来。我们的目标将 然后是：(1)与DLPFC的RNA-SEQ一起对这两个脑区进行病例对照分析，以 识别与MDD相关的分子特征，并将我们的发现跨分子图谱整合到 提供对MDD原因的更多机械性见解；(2)利用最近发现的 全基因组范围内对MDD及其密切相关特征神经质的GWAS研究的重大发现，到精细- 定位相关基因座并识别表达数量性状基因座(EQTL)以及甲基化和/或变化 可能介导遗传标记与表达之间的关联的染色质；(3)执行病例- MDD自杀与自然死亡病例对比分析 导致确定与自杀有关的分子特征和机制；以及，最后，(4)执行 在50个病例和50个对照的独立样本中重复主要发现。为了确保 这项提议的成功，我们已经从约翰斯那里组建了一支强大的跨学科调查小组 霍普金斯情绪障碍研究小组和利伯研究所为大脑发育而设立，拥有情绪方面的专业知识 疾病、基因组学、死后脑研究和统计遗传学。通过调查功能 MDD的基因组学和表观基因组学在大量且特征良好的死后脑标本中的研究 在识别基因和网络方面具有很强的潜力，这些基因和网络可能成为新一代 治疗。

Major Depressive Disorder (MDD) is a frequently recurring disorder that is the second leading cause of disability worldwide and a significant risk factor for suicide. Despite better recognition and increased treatment, the prevalence of MDD and the overall rates of suicide remain unchanged. Although a wide variety of treatments are available, their overall efficacy remains modest, and only a third of treated patients show full remission. Novel treatments are urgently needed, yet the development of new types of antidepressants has been hindered by our limited understanding of the pathophysiology of MDD. In this proposal, we seek to perform the largest and most comprehensive molecular study of MDD in post-mortem brains to date. We will use the substantial post-mortem brain collection of the Lieber Institute for Brain Development to comprehensively study genome-wide expression and epigenetic signatures that are associated with MDD and suicide in the three brains regions of the corticolimbic circuit, consisting of the Anterior Cingulate Cortex (ACC), the Amygdala, and the Dorsal Lateral Prefrontal Cortex (DLPFC). We propose to perform RNA sequencing, DNA-methylation and chromatin accessibility (ATAC-seq) assays in the ACC and Amygdala of 400 post- mortem brain samples and to combine these results with of the DLPFC from Brainseq project. Our aims will then be to: (1) conduct case-control analyses of these two brain regions along with RNA-seq of the DLPFC to identify molecular signatures associated with MDD and integrate our findings across molecular profiles to provide additional mechanistic insights into the causes of MDD; (2) to take advantage of recent identification of genome-wide significant findings from GWAS studies in MDD and its closely related trait, neuroticism, to fine- map associated loci and identify expression quantitative trait loci (eQTLs) and changes in methylation and/or chromatin that may mediate the association between genetic marker and expression; (3) to perform a case- only analysis of the cases with MDD who died by suicide compared with cases with MDD who died by natural causes to identify molecular signatures and mechanisms associated with suicide; and, finally (4) to perform a replication of the main findings in an independent sample of 50 cases and 50 controls. In order to ensure the success of this proposal, we have assembled a strong interdisciplinary investigative team from the Johns Hopkins Mood Disorder research group and the Lieber Instituted for Brain development, with expertise in mood disorders, genomics, post-mortem brain studies, and statistical genetics. By investigating the functional genomics and epigenomics of MDD in a large and well characterized post-mortem brain collection, our study has strong potential to identify genes and networks that could be novel targets for a new generation of treatments.