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）是一种经常复发的疾病，是导致抑郁症的第二大原因。 世界范围内的残疾和自杀的重要风险因素。尽管得到了更好的认识和更多的治疗， 抑郁症的患病率和自杀的总体比率保持不变。尽管各种各样的 尽管有治疗方法可用，但其总体疗效仍然适中，只有三分之一的治疗患者表现出完全的 缓解。新的治疗方法是迫切需要的，但新型抗抑郁药的发展， 由于我们对MDD的病理生理学了解有限，在本建议中，我们力求 进行迄今为止最大和最全面的死后大脑MDD分子研究。我们将 利用利伯大脑发育研究所的大量死后大脑样本， 全面研究与MDD相关的全基因组表达和表观遗传特征， 自杀发生在皮层边缘回路的三个大脑区域，包括前扣带皮层（ACC）， 杏仁核和背外侧前额叶皮质（DLPFC）。我们建议进行RNA测序， 400例受试者的ACC和杏仁核中的DNA甲基化和染色质可及性（ATAC-seq）测定， 尸检大脑样本，并将这些结果与Brainseq项目的DLPFC结合联合收割机。我们的目标将 然后是：（1）对这两个脑区进行病例对照分析，沿着DLPFC的RNA-seq， 识别与MDD相关的分子特征，并整合我们在分子谱中的发现， 为MDD的原因提供额外的机械见解;（2）利用最近识别的 GWAS在MDD及其密切相关的特征，神经质，精细， 绘制相关基因座并鉴定表达数量性状基因座（eQTL）和甲基化和/或 可能介导遗传标记与表达之间关联的染色质;（3）进行病例- 仅分析自杀死亡的MDD病例与自然死亡的MDD病例 找出与自杀有关的分子特征和机制;最后（4）进行一项 在50例病例和50例对照的独立样本中复制主要结果。为确保 这项建议的成功，我们已经组建了一个强大的跨学科的调查小组，从约翰 霍普金斯情绪障碍研究小组和利伯大脑发育研究所，在情绪方面的专业知识 疾病，基因组学，死后大脑研究和统计遗传学。通过调查功能 在一个大的和良好的特点死后大脑收集MDD的基因组学和表观基因组学，我们的研究 具有很强的潜力，可以识别基因和网络，这些基因和网络可能成为新一代免疫缺陷病毒的新靶点。 治疗。