Dissecting Causal Role of Insomnia in Cardiovascular Disease

项目摘要/摘要 失眠障碍发生在10%-20%的人群中，并使事故的原因风险增加2倍 心血管疾病(CVD)基于我们最近的孟德尔随机研究。寻找新的治疗方法 作为改善心血管疾病风险的失眠靶点，剖析失眠的病因病理生理学很重要。 并区分心血管疾病风险的增加是由共同的因果机制还是特定的心血管疾病引起的 失眠状态引起的侮辱。这一建议是由一个研究问题推动的：失眠是如何 导致心血管疾病增加，应针对哪些具体的失眠机制来预防或延缓心血管疾病？ 我们发现了57个全基因组范围内与失眠有关的显著遗传位点，并与心血管疾病建立了牢固的因果联系， 但需要更好地理解特定的共同因果路径和机械链接才能移动 走向个性化、有效的治疗方法。最近的模型生物体研究描述了特定的机制联系 睡眠、免疫、动脉粥样硬化和心血管疾病之间的关系，我们也可以测试这些疾病的相关性 在人类中破译收敛机制。因此，在这里，我们建议利用基因组测序和 来自TopMed的多种族样本的整合多组学和英国生物库Focus的外显子组测序 果蝇睡眠和心血管功能的功能研究寻找致病基因并鉴定 将失眠与心血管疾病联系起来的机制。我们提出了以下具体目标：1)找出因果关系 57个基因建立了失眠的遗传位点，并剖析了潜在的疾病机制和途径 人类(NHLBI TopMed和UK Biobank)。多种族精细绘图和稀有变异分析将精准 由多性状关联提供信息的因果基因和软聚类分析将识别异质性 失眠症的发病机制和亚型。2)检测果蝇功能丧失的后果 导致人类失眠的基因对睡眠和心血管功能的影响。表型效应与基因 表达模式将被系统地描述，以揭示重要的功能途径和网络。 3)测试睡眠紊乱(被扰乱或改善)对心血管疾病的发病率和进展的影响 果蝇利用小分子、遗传-机械扰动和限时饲养利用 人类整合多组学(NHLBI TopMed)。我们的项目将入围与治疗相关的基因和 将失眠、睡眠和心血管疾病联系起来的通路。

Project Summary/Abstract Insomnia disorder occurs in 10-20% of the population and confers a >2-fold increased causal risk of incident cardiovascular disease (CVD) based on our recent Mendelian randomization studies. To identify new therapeutic targets for insomnia that ameliorate CVD risk, it is important to dissect the causal pathophysiology of insomnia and distinguish whether increased CVD risk arises from shared causal mechanisms or specific cardiovascular insults induced by the insomnia state. This proposal is motivated by the research question: how does insomnia lead to increased CVD and what specific mechanisms of insomnia should be targeted to prevent or delay CVD? We found 57 genome-wide significant genetic loci for insomnia and established robust causal links with CVD, but need improved understanding of specific shared causal pathways and mechanistic links in order to move towards personalized, effective therapies. Recent model organism studies describe specific mechanistic links between sleep, immunity, atherosclerosis and cardiovascular disease that we can also test for disease relevance in people to decipher convergent mechanisms. Thus, here we propose to leverage genome-sequencing and integrative multi-omics in multi-ethnic samples from TopMed and exome sequencing in UK Biobank with focused functional studies of sleep and cardiovascular function in Drosophila to find the causal genes and identify mechanisms that causally link insomnia to CVD. We propose the following Specific Aims: 1) To pinpoint causal genes at 57 established insomnia genetic loci and dissect underlying disease mechanisms and pathways in humans (NHLBI TopMed and UK Biobank). Multi-ethnic fine-mapping and rare variant analysis will pinpoint causal genes and soft clustering analysis informed by multi-trait associations will identify heterogeneous insomnia disease mechanisms and subtypes. 2) To test the consequence of the loss of function of the Drosophila orthologs of causal human insomnia genes on sleep and cardiovascular function. Phenotypic effects and gene expression patterns will be systematically characterized to unravel important functional pathways and networks. 3) To test the impact of perturbed sleep (disrupted or improved) on incidence and progression of CVD in Drosophila using small molecule-, genetic- mechanical perturbation and time-restricted feeding and using integrative multi-omics in humans (NHLBI TopMed). Our project will shortlist therapeutically-relevant genes and pathways that link insomnia, sleep and CVD.