Using integrated omics to identify dysfunctional genetic mechanisms influencing schizophrenia and sleep disturbances

使用整合组学来识别影响精神分裂症和睡眠障碍的功能失调的遗传机制

• 批准号: 10770880
• 负责人: Steven Allan Soper
• 金额: $ 25.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2024-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10770880
• 关键词: Biochemical Genetics; Biochemical Pathway; Brain; Brain region; Caring; Communities; Data; Diagnosis; Disease; Drug Targeting; Early Diagnosis; Early Intervention; Female; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genomics; Goals; Human; Individual; Investigation; Kansas; Knowledge; Medical; Medical center; Mental Health; Multiomic Data; Outcome; Patients; Pharmacogenetics; Proteins; Proteome; Race; Reporting; Research Personnel; Resources; Risk; Schizophrenia; Severities; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Specimen; Symptoms; Universities; Variant; Work; improved; male; neurodevelopment; pleiotropism; precision medicine; risk prediction; sample collection; sleep behavior; sleep regulation; small molecule; transcriptome

The proposed work aims to decipher genetic factors dysregulated in the brains of individuals with schizophrenia with pleiotropic effects influencing sleep issues. The goals are to inform genomic driven medical care for improved treatment of sleep problems, which are among the most common co-occurring conditions in these patients. Sleep disruptions are associated with more severe schizophrenia-related symptoms. Healthy sleep is important for neurodevelopment, indicating that managing sleep disturbances may have significant impacts on reducing severity of schizophrenia symptoms and improving long-term outcomes. Characterizing pleiotropic genetic effects using multiomics data holds promise for informing precision medicine approaches to treatment of sleep problems in these individuals. Investigators at the University of Kansas Medical Center have whole brain specimens from human donors diagnosed with schizophrenia and confirmed controls. This brain bank reflects a diverse collection of specimens from males and females with different reported race. This project will generate multi-omics data from sleep-wake regulating brain regions in these specimens and identify genetic variation impacting function of pleiotropic genes and proteins evidenced to increase risk for both schizophrenia and insomnia-related symptoms. Variants with evidence for pharmacogenetic and regulatory effects on genes encoding drug targets will be evaluated. Genetic risk scores calculated from sequence data that are useful to predicting risk and aiding in early detection and intervention will be functionally validated. In addition, this project will comprehensively characterize gene and protein coexpression connecting two important brain regions known to regulate human sleep behaviors. Combining evidence from the genome, transcriptome and proteome will allow for discerning the biochemical pathways and genetic mechanisms dysregulated in sleep-wake regulating brain regions from these patients and help identify proteins that can be targeted by small molecule compounds to treat sleep problems more effectively. This work should also provide knowledge of how convergent mechanisms influence risk for multiple disorders in the same individual. The approaches developed and data generated in this project will provide a rich resource that will be shared with the larger scientific community allowing for investigations of the sleep regulation network in a diverse representation of individuals with mental health conditions.

这项工作旨在破译患有此类疾病的个体大脑中失调的遗传因素。 精神分裂症具有影响睡眠问题的多效性。目标是告知基因组驱动的 改善睡眠问题治疗的医疗护理，这是最常见的并发问题之一 这些患者的情况。睡眠中断与更严重的精神分裂症相关 症状。健康的睡眠对于神经发育很重要，这表明管理睡眠障碍 可能对减轻精神分裂症症状的严重程度和改善长期症状产生重大影响 结果。使用多组学数据表征多效性遗传效应有望提供信息 精准医学方法来治疗这些人的睡眠问题。调查人员在 堪萨斯大学医学中心拥有来自被诊断患有以下疾病的人类捐赠者的全脑标本 精神分裂症和确认的对照。这个脑库反映了来自不同国家的不同样本的集合 报告种族不同的男性和女性。该项目将生成多组学数据 睡眠-觉醒调节这些样本的大脑区域，并识别影响功能的遗传变异 多效性基因和蛋白质被证明会增加精神分裂症和失眠相关的风险 症状。具有药物遗传学和药物编码基因调节作用证据的变体 将评估目标。根据有助于预测的序列数据计算遗传风险评分 风险以及早期发现和干预的帮助将得到功能验证。此外，该项目将 全面表征连接两个重要大脑区域的基因和蛋白质共表达 已知可以调节人类睡眠行为。结合基因组、转录组和 蛋白质组将有助于辨别生物化学途径和遗传机制失调 睡眠-觉醒调节这些患者的大脑区域，并帮助识别可以靶向的蛋白质 小分子化合物可以更有效地治疗睡眠问题。这项工作还应该提供 了解收敛机制如何影响同一个体多种疾病的风险。 该项目中开发的方法和生成的数据将提供丰富的资源 与更大的科学界共享，以便对睡眠调节网络进行研究 患有心理健康问题的个体的多样化代表。