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Modeling the interaction of physiological and environmental stressors on common variants to psychiatric traits

模拟生理和环境压力源对精神特征常见变异的相互作用

基本信息

批准号：
10337629
负责人：
Kristen Jennifer Brennand
金额：
$ 75.73万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337629
关键词：
Affect Alleles American Astrocytes Biological Brain Brain Diseases Cell physiology Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Data Set Diagnosis Diagnostic Disease Dissection Engineering Environment Environmental Exposure Environmental Risk Factor Etiology FURIN gene Gene Targeting Genes Genetic Genetic Risk Genetic Screening Genome engineering Genomics Goals Healthcare Heritability Human Hydrocortisone In Vitro Interferon-alpha Interleukin-6 Lead Link Measures Medical Mental disorders MicroRNAs Microglia Modeling Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Nucleic Acid Regulatory Sequences Outcome Pathway interactions Patients Phenotype Physiological Schizophrenia Severities Stimulus Stress Testing Therapeutic Intervention Translations Untranslated RNA Validation Variant Work base biobank bisphenol A brain cell causal variant cell type clinical predictors clinically actionable combinatorial disorder risk environmental stressor falls follow-up functional genomics gene environment interaction genetic association genetic disorder diagnosis genetic variant genome wide association study improved insight neglect neurogenomics novel therapeutic intervention phenome phthalates physiologic stressor polygenic risk score population based precision medicine psychogenetics response risk variant stressor synaptic function therapeutic target trait transcriptome transcriptomics translational impact treatment response

项目摘要

PROJECT SUMMARY Psychiatric and neurodegenerative disorders are highly heritable and debilitating brain diseases that together affect nearly fifty million Americans, caused by the complex interaction of genetic and environmental risk factors. Although genomic studies indicate that much of disease risk reflects the aggregate impact of hundreds of genetic variants, to date, a substantial proportion of both the heritable and environmental components remain unexplained. A major challenge in the field has been illuminating the pathways connecting genetic variants (the vast majority of which fall in non-coding sequences) to target genes and causal cellular phenotypes, particularly in a cell-type-specific and context-dependent manner. We previously uncovered an unexpected combinatorial effect between risk genes that was not predicted from single gene perturbations, one that concentrated on synaptic function and linked the rare and common variant genes implicated in psychiatric disease risk. Based on our preliminary analyses and the work of others, we hypothesize that impact of genetic variants and stress converge and interact to impact critical neuronal and glia functions. Here our objective is to evaluate psychiatric and neurodegenerative risk variants, investigating convergent relationships between risk variants and stress across the major cell types of the brain. To do this, we will functionally dissect the impact of genetic variants significantly associated with brain disease, exploring their regulatory impact across cell types (neurons, astrocytes, glia) and contexts (physiological and environmental stressors) (Aim 1). To extend these insights, we will explore additive effects between risk variants and stressors at the level of network expression and cellular function (Aim 2). Finally, to test the extent that these insights might result in clinically actionably information, we will the clinical consequences of gene-environment interactions across two large healthcare and population- based biobanks (Aim 3). The translational impact of our work includes potential improvements to additive polygenic risk scores, prioritization of convergent genes for mechanistic follow-up, and identification of pathways that might serve as potential therapeutic targets. Our overarching goal is to advance the field towards an era of precision medicine, whereby not just each patient’s genetic variants, but also the expected interactions between them, can be used to predict disease trajectory and potential therapeutic interventions.

项目摘要精神和神经退行性疾病是高度遗传性和衰弱性脑部疾病，影响近5000万美国人，由遗传和环境风险因素的复杂相互作用引起。尽管基因组研究表明，许多疾病风险反映了数百种遗传因素的综合影响，变异，迄今为止，遗传和环境成分的相当大的比例仍然存在无法解释该领域的一个主要挑战是阐明连接遗传变异的途径（其中绝大多数属于非编码序列）靶向基因和致病细胞表型，特别是以小区类型特定和上下文相关的方式。我们之前发现了一个意想不到的组合风险基因之间的影响，不能从单基因扰动预测，一个集中在突触功能，并将涉及精神疾病风险的罕见和常见变异基因联系起来。基于根据我们的初步分析和其他人的工作，我们假设遗传变异和压力的影响汇聚并相互作用，影响关键的神经元和神经胶质功能。我们的目标是评估精神病学和神经退行性风险变异，研究风险变异和压力之间的收敛关系在大脑的主要细胞类型中。为此，我们将从功能上剖析遗传变异的影响与脑疾病显著相关，探索它们对细胞类型（神经元，星形胶质细胞，神经胶质细胞）和上下文（生理和环境应激）（目标1）。为了扩展这些见解，我们将探讨风险变量和压力源之间的网络表达和细胞水平的加性效应功能（目标2）。最后，为了测试这些见解可能导致临床可操作信息的程度，我们基因与环境相互作用对两个大型医疗保健和人口的临床后果- 基于生物库（目标3）。我们工作的转化影响包括对添加剂的潜在改进。多基因风险评分，用于机械随访的聚合基因的优先级，以及途径的识别可能成为潜在的治疗靶点我们的首要目标是将该领域推向一个精准医学，不仅是每个病人的遗传变异，而且是预期的相互作用，它们可用于预测疾病轨迹和潜在的治疗干预。