Neural and Genetic Basis of Negative Valance Traits

描述(由申请人提供)：目前对精神障碍的分类是基于对体征和症状的分类，而没有考虑潜在的神经生物机制。这些类别的具体化限制了人们对导致各种形式的精神病理学的基本行为、神经和遗传机制的理解。为了解决机制和病因学之间的这种脱节，NIMH最近启动了RDoC项目，以促进对精神病理学采取更“自下而上”的方法。我们的建议聚焦于RDoC矩阵的“负价”域，旨在表征和验证“焦虑”结构(“对潜在威胁的反应”)的神经表型。在一个独特的大型神经影像资源(MGH基因组超结构计划，GSP)中，我们最近发现了边缘系统完整性的神经测量(杏仁核增大和内侧前额叶皮质[mPFC]变薄)，它与特质焦虑的维度测量密切相关。根据RDoC框架的目标，我们现在建议分三个阶段验证这一焦虑维度的关键生物学和临床特征：1)临床特征：我们将证明这种神经表型与临床人群表现出显著焦虑症状的相关性及其与症状严重性、慢性化和功能障碍的关系；2)神经解剖：我们将使用先进的Connectome成像技术来检查焦虑神经表型与mPFC和特定杏仁核亚核之间的白质连接之间的关系；3)基因解剖：利用普通和罕见(外显子组阵列)全基因组数据(N=2078)，我们将进行单变异、基因组分割和生物通路分析，以确定等位基因对焦虑症神经表型的贡献，并表征贡献基因座的总遗传力和生物学意义。这些目标的成功完成将对RDoC焦虑维度的神经、行为和遗传基础产生新的见解，并为RDoC的目标--基于病因学和发病机制的精神病学分类新框架--迈出关键的一步。

DESCRIPTION (provided by applicant): The current classification of psychiatric disorders is based on categorical clustering of signs and symptoms, without regard to underlying neurobiologic mechanisms. The reification of these categories has constrained efforts to develop an understanding of the fundamental behavioral, neural and genetic mechanisms that give rise to various forms of psychopathology. To address this disconnect between mechanism and nosology, the NIMH recently launched the RDoC project to facilitate a more "bottom up" approach to psychopathology. Our proposal focuses on the "negative valence" domain of the RDoC matrix and aims to characterize and validate a neural phenotype of the "Anxiety" construct ("response to potential threat"). In a uniquely large neuroimaging resource (the MGH Genomic Superstruct Project, GSP) we have recently identified a neural measure of limbic system integrity (amygdala enlargement and medial prefrontal cortical [mPFC] thinning) that is robustly associated with dimensional measures of trait anxiety. Consistent with the goals of the RDoC framework, we now propose to validate key biological and clinical features of this anxiety dimension in three stages: 1) Clinical Characterization: we will demonstrate the relevance of this neural phenotype to clinical populations presenting with significant anxiety symptoms and its association with symptom severity, chronicity and functional impairment; 2) Neural Dissection: we will use advanced Connectome imaging technology to examine the relationship between the anxiety neural phenotype and white matter connectivity between the mPFC and specific amygdala subnuclei; and 3) Genetic Dissection: using common and rare (exome array) genomewide data (N = 2078), we will conduct single variant, genome partitioning, and biological pathway analyses to identify allelic contributions to the anxiety neural phenotype and characterize the aggregate heritability and biological significance of contributing loci. Successfu completion of these aims will yield novel insights into the neural, behavioral, and genetic basis of the RDoC anxiety dimension and provide a crucial step towards the RDoC's goal of a new framework for psychiatric classification grounded in etiology and pathogenesis.