Dimensional Neurogenetic Markers of Limbic System Integrity & Psychiatric Illness

边缘系统完整性的维度神经遗传标记

• 批准号: 8581402
• 负责人: AVRAM J HOLMES
• 金额: $ 15.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581402
• 关键词: Accounting; Affect; Affective; Amygdaloid structure; Anatomy; Anxiety; Anxiety Disorders; Architecture; Area; Award; Behavior; Behavioral; Biological; Bipolar Disorder; Brain; Characteristics; Clinical; Clinical Skills; Complex; Coupling; Data; Data Set; Development; Diagnosis; Diagnostic; Disease; Emotions; Environment; Equipment; Etiology; Foundations; General Hospitals; General Population; Genetic; Genetic Research; Genetic Risk; Goals; Health; Heterogeneity; Human Genetics; Image; Impairment; Individual; Individual Differences; Knowledge; Limbic System; Link; Literature; Maintenance; Major Depressive Disorder; Massachusetts; Measures; Medial; Mental disorders; Mentorship; Methods; Molecular Genetics; Mood Disorders; Nature; Neurosciences; Pathway interactions; Pattern; Perception; Personality; Phenotype; Population; Prefrontal Cortex; Process; Psychiatric Diagnosis; Psychiatry; Regulation; Research; Research Personnel; Resources; Rest; Risk; Risk Factors; Role; Site; Social Functioning; Symptoms; System; Thick; Training; Variant; Work; base; bioimaging; career; case control; design; disorder risk; genetic variant; genome wide association study; image processing; imaging modality; neurogenetics; neuroimaging; novel; programs; public health relevance; relating to nervous system; risk variant; social; tool; young adult

DESCRIPTION (provided by applicant): Psychiatric diagnoses are complex and heterogeneous constructs. Rather than natural kinds, they describe clusters of frequently co-occurring symptoms, which often lack a distinct border between health and disease. This makes it difficult to establish if a dysregulation within a particular brain system contributes to the intial occurrence of an illness, or emerges as a result of pathophysiological processes following onset. Here we propose parsing the heterogeneity of anxiety and affective disorders through the identification of neural and genetic pathways associated with illness risk, onset, and maintenance. With a focus on amygdala-medial prefrontal cortex (mPFC) circuitry, this project will: (1) Establish relations between dimensional measures of affective and social functioning and amygdala-mPFC circuit integrity in psychiatrically healthy treatment naive young adults; (2) Identify associations between previously validated polygenic risk factors for affective illnesses, derived through large-scale case-control GWAS analyses, and amygdala-mPFC circuit integrity; and (3) Establish novel polygenic scores that co-vary with the anatomical and intrinsic integrity of amygdala-mPFC circuitry in healthy young adults, assessing the relations between these scores and the presence of psychiatric illness in an independent case-control dataset. The genetic and biological architecture of the major psychiatric disorders remains largely unknown. The proposed research may enable the identification of new genetic variants, anatomical features, or patterns of brain activity that are characteristic of certain disorders. The identification of novel biological pathways, even ones that contribute a small increment of risk, can suggest new etiological hypotheses and possible treatment targets. Dr. Avram Holmes' primary career goal is to study biological pathways contributing to individual differences in psychiatric illness risk. The proposed project will allow Dr. Holmes to receive training in genetics, advanced imaging methods, and systems neuroscience. In doing so he will develop a translational inter-disciplinary research program that combines molecular genetic and neuroimaging methods. The project will be conducted in the Department of Psychiatry at Massachusetts General Hospital. The specific research sites include the Athinoula A. Martinos Center for Biomedical Imaging and the Center for Human Genetic Research. The associated facilities, resources and environment provide the equipment, space and expertise required for the execution of this research. The proposed project, associated training, and mentorship will form the foundation of Dr. Holmes' independent research program, which will have anxiety and affective disorders as a core clinical focus.

描述（由申请人提供）：精神病学诊断是复杂且异质的结构。它们描述的不是自然类型，而是经常同时出现的症状群，这些症状通常缺乏健康与疾病之间的明显界限。这使得很难确定特定大脑系统内的失调是否导致疾病的最初发生，或者是由于发病后病理生理过程而出现。在这里，我们建议通过识别与疾病风险、发病和维持相关的神经和遗传途径来解析焦虑和情感障碍的异质性。该项目重点关注杏仁核-内侧前额叶皮层 (mPFC) 回路，将：(1) 在未接受过精神健康治疗的年轻人中，建立情感和社会功能的维度测量与杏仁核-mPFC 回路完整性之间的关系； (2) 通过大规模病例对照 GWAS 分析得出先前验证的情感疾病多基因危险因素与杏仁核-mPFC 回路完整性之间的关联； (3) 建立与健康年轻人杏仁核-mPFC回路的解剖学和内在完整性共同变化的新的多基因评分，在独立的病例对照数据集中评估这些评分与精神疾病之间的关系。主要精神疾病的遗传和生物学结构在很大程度上仍然未知。拟议的研究可能能够识别新的遗传变异、解剖特征或某些疾病特征的大脑活动模式。新的生物学途径的识别，即使是那些导致风险小幅增加的途径，也可以提出新的病因学假设和可能的治疗目标。阿夫拉姆·霍姆斯博士的主要职业目标是研究导致精神疾病风险个体差异的生物途径。拟议的项目将使霍姆斯博士能够接受遗传学、先进成像方法和系统神经科学方面的培训。为此，他将开发一个结合分子遗传学和神经影像方法的转化性跨学科研究项目。该项目将在马萨诸塞州总医院精神病学部进行。具体研究地点包括Athinoula A. Martinos生物医学成像中心和人类基因研究中心。相关设施、资源和环境提供了执行这项研究所需的设备、空间和专业知识。拟议的项目、相关培训和指导将构成霍姆斯博士独立研究计划的基础，该计划将以焦虑和情感障碍作为核心临床重点。