Neural and Genetic Basis of Negative Valance Traits

描述（由申请人提供）：目前精神疾病的分类是基于体征和症状的分类聚类，而不考虑潜在的神经生物学机制。这些范畴的具体化限制了对引起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。为了解决机制和疾病分类学之间的脱节，NIMH最近启动了RDoC项目，以促进精神病理学更“自下而上”的方法。我们的建议侧重于RDoC矩阵的“负效价”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基因组超结构项目，GSP），我们最近确定了边缘系统完整性的神经措施（杏仁核扩大和内侧前额叶皮层[mPFC]变薄），这是强大的特质焦虑维度的措施。与RDoC框架的目标一致，我们现在建议分三个阶段验证这种焦虑维度的关键生物学和临床特征：1）临床表征：我们将证明这种神经表型与临床人群的相关性，这些人群表现出显著的焦虑症状及其与症状严重程度，慢性和功能障碍的相关性; 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色物质连接之间的关系;以及3）遗传解剖：使用常见和罕见（外显子组阵列）全基因组数据（N = 2078），我们将进行单变异，基因组划分，和生物学途径分析，以鉴定对焦虑神经表型的等位基因贡献，并表征贡献基因座的总遗传力和生物学意义。这些目标的顺利完成将产生新的见解的神经，行为和遗传基础的RDoC焦虑维度，并提供了一个关键的一步RDoC的目标，一个新的框架，精神病分类的病因和发病机制。

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.