Neurogenetic Investigations of Obsessive-Compulsive Disorder

强迫症(OCD)是一种致残性早发性神经精神障碍，其病因不明 潜在的病理生理学，这阻碍了新的治疗和干预措施的发展。而当 强迫症的风险有明显的遗传因素，几十年的研究尚未得出可重复性的结果， 具有统计学意义的发现，已经确定了高置信度风险基因。利用遗传学的研究进展 澄清生物学可能受到多种因素的阻碍，包括对共同基因的狭隘关注 效应大小较小的变种，动力不足的研究设计，对光谱的普遍不确定性 应该质疑的遗传变异，并限制对下游基因表达和相关基因的关注 在相关组织中驱动基因表达的表观遗传特征。迫切需要进一步的努力。 使用替代方法来识别和确认风险基因，这将为强迫症生物学提供见解。这个 目前提案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，检测强迫症的基因表达差异，并确定驱动基因的表观遗传特征 在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建议(A) 500例高可信风险基因全外显子测序和从头检测的研究 强迫症亲子三人组和500个对照三人组；(B)使用来自475个强迫症的合作者数据复制这些分析 三名强迫症先证者和1,000名强迫症先证者；以及(C)将强迫症风险基因纳入系统分析，以确定丰富的 基因网络、途径和时空表达模式。目标2建议鉴定体细胞花叶 来自所有强迫症和对照三人组以及来自外周血和脑组织的外显子组测序数据中的变异 来自10名强迫症受试者。目的3建议鉴定差异表达基因和染色质 10例强迫症患者和10例配对对照受试者脑组织中的特征 ATAC-SEQ.这项拟议的研究试图通过一系列的研究来填补我们对强迫症生物学知识的空白 具体涉及《国家卫生和环境卫生战略计划》目标1的研究(确定 复杂的行为)。如果成功，这项研究将改变我们对潜在机制的理解 并为模型系统中的力学研究确定牵引点，最终导致新的 治疗，并降低与这一致残性疾病相关的显著发病率和死亡率。 此外，在这些研究中获得的洞察力可以为其他复合体的基因发现方法提供参考 神经精神障碍。

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.