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.

项目摘要精神病和神经退行性疾病是高度遗传和使人衰弱的脑部疾病由遗传和环境风险因素的复杂相互作用引起的近五千万美国人。尽管基因组研究表明，疾病的大部分风险反映了数百种遗传的总体影响迄今无法解释。该领域的一个主要挑战一直在阐明连接遗传变异的途径（绝大多数属于非编码序列），以靶向基因和因果细胞表型，尤其是以细胞类型特异性和上下文依赖性方式。我们以前发现了意外的组合从单个基因扰动预测的风险基因之间的影响，该基因集中在一个基因上突触功能，并将精神病风险实施的稀有和常见变体基因联系起来。基于我们的初步分析和他人的工作，我们假设遗传变异和压力的影响收敛并相互作用以影响关键的神经元和神经胶质功能。在这里我们的目标是评估精神病学和神经退行性风险变体，研究风险变异与压力之间的收敛关系跨大脑的主要细胞类型。为此，我们将在功能上剖析遗传变异的影响与大脑疾病显着相关，探索它们在细胞类型（神经元，星形胶质细胞，神经胶质）和环境（生理和环境压力源）（AIM 1）。为了扩展这些见解，我们将探索在网络表达水平和细胞水平上的风险变体和压力源之间的其他效果功能（AIM 2）。最后，为了测试这些见解可能会导致临床上可行的信息的程度，我们在两个大型医疗保健和人群中，基因环境相互作用会带来临床后果基于生物库（AIM 3）。我们工作的翻译影响包括对添加剂的潜在改进多基因风险评分，用于机械随访的收敛基因的优先级以及识别途径这可能是潜在的治疗靶标。我们的总体目标是将领域推进到一个时代精密药物不仅是每个患者的遗传变异，而且还它们可用于预测疾病轨迹和潜在的治疗干预措施。