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

项目总结 精神和神经退行性疾病是高度可遗传的和衰弱的脑部疾病 影响到近5000万美国人，是由遗传和环境风险因素复杂相互作用造成的。 尽管基因组研究表明，许多疾病风险反映了数百种基因的综合影响 到目前为止，可遗传和环境成分中的相当大一部分仍然是变种 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)，以靶向基因和原因细胞表型，特别是 以特定于细胞类型且依赖于上下文的方式。我们之前发现了一种意想不到的组合 没有从单基因扰动中预测到的风险基因之间的影响，集中在 突触功能，并将与精神疾病风险有关的罕见和常见变异基因联系起来。基于 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细胞功能。我们的目标是评估精神病学 和神经退行性风险变量，研究风险变量和压力之间的趋同关系 横跨大脑的主要细胞类型。为了做到这一点，我们将从功能上剖析基因变异的影响 与脑部疾病显著相关，探索它们在细胞类型(神经元、 星形胶质细胞)和环境(生理和环境应激源)(目标1)。为了推广这些见解，我们 将在网络表达和细胞水平上探索风险变量和应激源之间的相加效应 功能(目标2)。最后，为了测试这些洞察力可能在多大程度上导致临床上可操作的信息，我们 两大医疗保健和人群中基因-环境相互作用的临床后果是否会- 基于生物库(目标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，机制随访的聚合基因的优先顺序，以及通路的识别 这可能会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 精确医学，不仅是每个患者的基因变异，而且还有预期的相互作用 它们可用于预测疾病轨迹和潜在的治疗干预措施。

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.