Integrative Genomics of the Corticolimbic Circuit in Major Depressive Disorder

重度抑郁症皮质边缘环路的综合基因组学

• 批准号: 10170424
• 负责人: Fernando Sampaio Goes
• 金额: $ 73.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170424
• 关键词: ATAC-seq; Affect; Amygdaloid structure; Anterior; Antidepressive Agents; Autopsy; Biological; Biological Assay; Biology; Bipolar Disorder; Brain; Brain region; Chromatin; Collaborations; Collection; DNA Methylation; Data; Data Set; Development; Disease; Disease remission; Distant; Dorsal; Elements; Ensure; Environment; Epigenetic Process; Etiology; Family; Functional disorder; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Marker Expression; Genetic Transcription; Genomics; Institutes; Knowledge; Lateral; Major Depressive Disorder; Maps; Mediating; Mental Depression; Mental disorders; Meta-Analysis; Methylation; Modality; Molecular; Molecular Profiling; Mood Disorders; Morbidity - disease rate; National Institute of Mental Health; Network-based; Neurobiology; Neurotic Disorders; Patients; Phenotype; Population; Prefrontal Cortex; Prevalence; Quantitative Trait Loci; Recording of previous events; Recurrence; Research; Research Personnel; Risk; Risk Factors; Sampling; Series; Structure; Suicide; Suicide attempt; Suicide prevention; Testing; base; brain tissue; case control; cingulate cortex; completed suicide; disability; drug development; early life adversity; epigenetic marker; epigenomics; functional disability; functional genomics; genetic analysis; genetic variant; genome wide association study; genome-wide; genome-wide analysis; insight; neurobiological mechanism; new therapeutic target; non-genetic; novel; novel therapeutic intervention; novel therapeutics; sample collection; success; suicidal risk; suicide rate; trait; transcriptome sequencing; transcriptomics

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.

重度抑郁症（MDD）是一种经常发生的疾病，是第二个主要原因 全世界的残疾和自杀的重要危险因素。尽管识别更好和治疗增加，但 MDD的患病率和自杀的总体率保持不变。虽然多种多样 可以接受治疗，其整体疗效仍然适中，只有三分之一的治疗患者显示出满 缓解。迫切需要新颖的治疗方法，但是新型抗抑郁药的发展具有 我们对MDD病理生理学的有限​​理解所阻碍。在此提案中，我们寻求 迄今为止，在验尸大脑中，对MDD进行最大，最全面的分子研究。我们将 使用Lieber大脑发育研究所的大量验尸大脑收集到 全面研究与MDD和MDD相关的全基因组表达和表观遗传特征 皮质降虫回路的三个大脑区域的自杀，由前扣带回皮质（ACC）组成 杏仁核和背侧前额叶皮层（DLPFC）。我们建议执行RNA测序， DNA-甲基化和染色质可及性（ATAC-SEQ）在ACC和杏仁核中的测定400分和杏仁核中 Mortem脑样本并将这些结果与BrainSeq项目的DLPFC结合在一起。我们的目标会 然后是：（1）进行这两个大脑区域的病例对照分析以及DLPFC的RNA-Seq 确定与MDD相关的分子特征，并将我们的发现跨分子曲线整合到 提供有关MDD原因的其他机械见解； （2）利用最近确定的 GWAS研究中的全基因组范围的重要发现及其密切相关的性状（神经质） 地图相关的基因座并识别表达定量性状基因座（EQTL）和甲基化和/或变化 可以介导遗传标记与表达之间的关联的染色质； （3）执行案例 - 仅对因自杀而死的MDD案件的分析与自然死亡的MDD案件相比 鉴定与自杀相关的分子特征和机制的原因；而且，最后（4）执行 在50例病例和50个对照的独立样本中重复主要发现。为了确保 该提议的成功，我们从约翰斯组成了一个强大的跨学科调查团队 霍普金斯情绪障碍研究小组和Lieber为大脑开发而建立，具有情绪专业知识 疾病，基因组学，验尸后脑研究和统计遗传学。通过研究功能 MDD的基因组学和表观基因组学在大型且验尸的大脑收集中，我们的研究 具有识别可能是新一代新一代目标的基因和网络的强大潜力 治疗。