Neurogenetic Investigations of Obsessive-Compulsive Disorder

强迫症的神经遗传学研究

• 批准号: 10053728
• 负责人: Thomas V Fernandez
• 金额: $ 59.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-10 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053728
• 关键词: ATAC-seq; Address; Adolescence; Attention; Automobile Driving; Behavior; Biological; Biological Models; Biological Process; Biology; Blood; Brain; Brain Diseases; Candidate Disease Gene; ChIP-seq; Characteristics; Child; Chromatin; Chronic; Complex; Data; Development; Disease; Epigenetic Process; Esthesia; Family Study; Functional disorder; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Goals; High-Throughput Nucleotide Sequencing; Intervention; Investigation; Knowledge; Link; Morbidity - disease rate; Mosaicism; National Institute of Mental Health; Nature; Neurobiology; Obsessive-Compulsive Disorder; Outcome; Parents; Pathway interactions; Patients; Pattern; Pharmacology; Prevalence; Process; Refractory Disease; Reproducibility; Research; Research Design; Risk; Series; Strategic Planning; Syndrome; Systems Analysis; Testing; Therapeutic Intervention; Thinking; Time; Tissues; Traction; Twin Studies; Uncertainty; Variant; Work; World Health Organization; autism spectrum disorder; base; brain tissue; chromatin modification; cohort; de novo mutation; differential expression; disorder control; disorder risk; early onset; exome sequencing; gene discovery; genetic risk factor; genetic variant; genome wide association study; improved; insight; knowledge base; mortality; neurogenetics; neuropsychiatric disorder; neuropsychiatry; new therapeutic target; novel; novel therapeutics; peripheral blood; predictive modeling; preservation; preventive intervention; proband; repetitive behavior; risk variant; spatiotemporal; transcriptome sequencing; variant detection; young adult

Obsessive-compulsive disorder (OCD) is a disabling early-onset neuropsychiatric disorder with unclear underlying pathophysiology, which has hindered the development of new treatments and interventions. While there is a clear genetic contribution to OCD risk, decades of investigations have yet to yield reproducible, statistically significant findings that have identified high-confidence risk genes. Progress in leveraging genetics to clarify biology has likely been impeded by multiple factors, including a narrow focus on common genetic variants with small effect sizes, underpowered study designs, general uncertainty about the spectrum of genetic variation that should be queried, and limited attention to downstream gene expression and associated epigenetic signatures that drive gene expression in relevant tissue. There is a critical need for further efforts using alternate approaches to identify and confirm risk genes that will provide insights into OCD biology. The overall objective of the current proposal is to use high-throughput sequencing approaches to identify OCD risk genes, detect gene expression differences in OCD, and determine epigenetic signatures driving gene expression in OCD brain. This will be accomplished by pursuing three specific aims. Aim 1 proposes to (a) identify high-confidence risk genes by whole-exome sequencing and de novo genetic variant detection in 500 OCD parent-child trios and 500 control trios; (b) replicate these analyses with collaborator data from 475 OCD trios and 1,000 OCD probands; and (c) integrate OCD risk genes into systems analyses to identify enriched gene networks, pathways, and spatiotemporal expression patterns. Aim 2 proposes to identify somatic mosaic variants in exome sequencing data from all OCD and control trios, and from peripheral blood and brain tissue from 10 OCD subjects. Aim 3 proposes identification of differentially expressed genes and chromatin signatures in brain tissue from 10 OCD and 10 matched control subjects using RNA-seq, ChIP-seq, and ATAC-seq. The proposed research attempts to close gaps in our knowledge of OCD biology by a series of studies that specifically addresses Objective 1 of the NIMH Strategic Plan (defining the mechanisms of complex behaviors). If successful, this research will transform our understanding of the underlying mechanisms of OCD and identify points of traction for mechanistic studies in model systems, ultimately leading to novel therapeutics, and reducing the significant morbidity and mortality associated with this disabling illness. Furthermore, insights gained in these studies can inform gene discovery approaches to other complex neuropsychiatric disorders.

强迫症（OCD）是一种残疾的早期神经精神疾病，不清楚 潜在的病理生理学阻碍了新疗法和干预措施的发展。尽管 对强迫症风险有明显的遗传贡献，数十年的调查尚未产生可重复的， 识别高信任风险基因的统计意义重大发现。利用遗传学的进展 为了阐明生物学可能受到多种因素的阻碍，包括对共同遗传的关注狭窄 具有较小效应尺寸的变体，功能不足的研究设计，关于光谱的一般不确定性 应该查询的遗传变异，并且对下游基因表达和相关的关注有限 在相关组织中驱动基因表达的表观遗传学特征。迫切需要进一步的努力 使用替代方法来识别和确认将为强迫症生物学提供见解的风险基因。这 当前建议的总体目标是使用高通量测序方法来识别强迫症风险 基因，检测OCD中的基因表达差异，并确定驱动基因的表观遗传特征 强迫症大脑中的表达。这将通过追求三个具体目标来实现。目标1提议（a） 通过全外病组测序和从头遗传变异检测确定高信任风险基因 强迫症亲子三重奏和500个控制三重奏； （b）使用来自475 OCD的合作数据来复制这些分析 三重奏和1,000个OCD概率； （c）将强迫症风险基因集成到系统分析中以识别丰富的 基因网络，途径和时空表达模式。 AIM 2建议识别体细节 从所有强迫症和控制三重奏以及外周血和脑组织的外显子组测序数据的变体 来自10个OCD主题。 AIM 3提出鉴定差异表达的基因和染色质 使用RNA-seq，chip-seq和 atac-seq。拟议的研究试图通过一系列一系列 专门针对NIMH战略计划的目标1的研究（定义的机制 复杂的行为）。如果成功，这项研究将改变我们对基本机制的理解 强迫症并识别模型系统机械研究的牵引力，最终导致新颖 治疗剂，并降低与这种残疾疾病相关的显着发病率和死亡率。 此外，在这些研究中获得的见解可以为基因发现方法告知其他复杂的方法 神经精神疾病。