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

基本信息

批准号：
9319305
负责人：
AVRAM J HOLMES
金额：
$ 14.67万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319305
关键词：
Accounting Affect Affective Alleles Amygdaloid structure Anatomy Anxiety Disorders Architecture Area Award Behavior Behavioral Biological Bipolar Disorder Brain Characteristics Clinical Complex Coupling Data Data Set Development Diagnosis Diagnostic Dimensions Disease Emotions Environment Equipment Etiology Foundations General Hospitals General Population Genetic Genetic Research Genetic Risk Goals Health Heritability Heterogeneity Human Genetics Impairment Individual Individual Differences Interdisciplinary Study Knowledge Limbic System Link Literature Maintenance Major Depressive Disorder Massachusetts Measures Medial Mental disorders Mentorship Methods Molecular Genetics Mood Disorders Nature Neurosciences Pathological anxiety 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 Temperament Thick Training Variant Work bioimaging career case control design disorder risk genetic variant genome wide association study image processing imaging genetics imaging modality negative affect neurogenetics neuroimaging novel programs public health relevance relating to nervous system risk variant skills social tool young adult

项目摘要

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）：精神病诊断是复杂且异质的结构。他们不是自然的，而是描述了经常出现的症状的簇，这些症状通常缺乏健康和疾病之间的独特边界。这使得难以确定特定大脑系统内的失调是否有助于疾病的态度发生，还是由于病理生理过程而导致的。在这里，我们建议通过鉴定与疾病风险，发作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。该项目着重于杏仁核中内皮层（MPFC）电路，该项目将：（1）建立情感和社会功能和社会功能的维度测量与杏仁核MPFC电路完整性之间的关系。（2）通过大规模的病例对照GWAS分析和杏仁核MPFC电路完整性确定了先前验证的情感疾病的多基因风险因素之间的关联；（3）建立新的多基因评分，与健康的年轻人中杏仁核MPFC电路的解剖学和内在完整性共同变化，评估了这些分数与独立病例控制数据集中精神病的存在之间的关系。主要精神疾病的遗传和生物结构在很大程度上仍然未知。提出的研究可以鉴定出新的遗传变异，解剖学特征或大脑活动的模式，这些特征是某些疾病的特征。鉴定新型生物学途径，即使是造成少量风险的生物学途径，也可以提示新的病因假设和可能的治疗靶标。 Avram Holmes博士的主要职业目标是研究导致精神病风险个体差异的生物学途径。拟议的项目将允许霍姆斯博士接受遗传学，高级成像方法和系统神经科学的培训。通过这样做，他将制定一个结合分子遗传和神经影像学方法的翻译跨学科研究计划。该项目将在马萨诸塞州综合医院的精神病学系进行。特定的研究地点包括Athinoula A. Martinos生物医学成像中心和人类遗传研究中心。相关的设施，资源和环境提供了执行本研究所需的设备，空间和专业知识。拟议的项目，相关的培训和指导将构成Holmes博士独立研究计划的基础，该计划将具有焦虑和情感障碍作为核心临床重点。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Myth of Optimality in Clinical Neuroscience.

DOI：
10.1016/j.tics.2017.12.006
发表时间：
2018-03
期刊：
Trends in cognitive sciences
影响因子：
19.9
作者：
Holmes AJ;Patrick LM
通讯作者：
Patrick LM

Gene expression links functional networks across cortex and striatum.

DOI：
10.1038/s41467-018-03811-x
发表时间：
2018-04-12
期刊：
Nature communications
影响因子：
16.6
作者：
Anderson KM;Krienen FM;Choi EY;Reinen JM;Yeo BTT;Holmes AJ
通讯作者：
Holmes AJ

Relationships between depressive symptoms and brain responses during emotional movie viewing emerge in adolescence.

DOI：
10.1016/j.neuroimage.2019.116217
发表时间：
2020-08-01
期刊：
NeuroImage
影响因子：
5.7
作者：
Gruskin DC;Rosenberg MD;Holmes AJ
通讯作者：
Holmes AJ

Reply to Risk and Zhu: Mixed-effects modeling as a principled approach to heritability analysis with repeat measurements.

回复Risk和Zhu：混合效应建模作为重复测量遗传力分析的原则方法。

DOI：
10.1073/pnas.1719882115
发表时间：
2018
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Ge,Tian;Holmes,AvramJ;Buckner,RandyL;Smoller,JordanW;Sabuncu,MertR
通讯作者：
Sabuncu,MertR