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.

提出的工作旨在破译遗传因素在患有 具有多效性影响的精神分裂症会影响睡眠问题。目标是告知基因组驱动的 改善睡眠问题治疗的医疗服务，这是最常见的同时发生的 这些患者的状况。睡眠中断与更严重的精神分裂症有关 症状。健康的睡眠对于神经发育很重要，表明管理睡眠障碍 可能对减少精神分裂症症状的严重程度有重大影响并改善长期 结果。使用多组分数据来表征多效性遗传效应有望告知 精密医学方法来治疗这些人的睡眠问题。调查人员 堪萨斯大学医学中心有诊断为人类捐助者的全脑标本 精神分裂症和确认的对照。该脑库反映了来自 报告种族不同的男性和女性。该项目将从 睡眠效果调节这些标本中的大脑区域并确定遗传变异影响功能 证据的多效基因和蛋白质可以增加精神分裂症和失眠有关的风险 症状。具有对编码药物基因的药物遗传学和调节作用的证据的变体 目标将进行评估。从序列数据计算出的遗传风险评分，这些数据对预测有用 风险和帮助早期检测和干预将在功能上进行验证。此外，这个项目将 全面地表征了连接两个重要大脑区域的基因和蛋白质共表达 已知可以调节人的睡眠行为。结合了基因组，转录组和 蛋白质组将识别生化途径和遗传机制失调 从这些患者中调节大脑区域的睡眠效果，并有助于鉴定可以针对的蛋白质 小分子化合物可以更有效地治疗睡眠问题。这项工作也应该提供 了解收敛机制如何影响同一个人多种疾病的风险。 该项目中开发的方法和数据将提供丰富的资源 与更大的科学界分享，允许对睡眠调节网络进行调查 具有心理健康状况的人的多样化代表。