Dissecting Causal Role of Insomnia in Cardiovascular Disease

项目总结/摘要 在10-20%的人群中发生胰岛素抵抗障碍，并使事件的因果风险增加2倍以上。 心血管疾病（CVD）是基于我们最近的孟德尔随机化研究。寻找新的治疗方法 失眠的目标是改善心血管疾病的风险，重要的是要解剖失眠的因果病理生理学 并区分CVD风险增加是否由共同的因果机制或特定的心血管疾病引起， 由失眠状态引起的侮辱。这个提议是由研究问题激发的：失眠是如何 导致心血管疾病的增加，失眠的具体机制应该针对什么来预防或延迟心血管疾病？ 我们发现了57个基因组范围内的失眠症重要遗传位点，并建立了与CVD的强有力的因果关系， 但需要更好地理解特定的共同因果途径和机制联系， 个性化的有效治疗最近的模式生物研究描述了特定的机制联系 睡眠、免疫力、动脉粥样硬化和心血管疾病之间的联系，我们也可以测试疾病的相关性， 来破译聚合机制因此，在这里，我们建议利用基因组测序， 来自TopMed的多种族样本中的整合多组学和英国生物库中的外显子组测序， 果蝇睡眠和心血管功能的功能研究，以找到致病基因，并确定 将失眠与心血管疾病联系起来的机制。我们提出以下具体目标：1）查明因果关系 基因在57个建立失眠遗传位点和解剖潜在的疾病机制和途径， 人类（NHLBI TopMed和UK Biobank）。多种族精细绘图和罕见变异分析将查明 通过多性状关联的因果基因和软聚类分析， 失眠症的发病机制及亚型。2)为了测试果蝇功能丧失的后果， 人类失眠症致病基因的直系同源物对睡眠和心血管功能的影响表型效应和基因 表达模式将被系统地表征，以揭示重要的功能途径和网络。 3)为了测试睡眠紊乱（中断或改善）对CVD发生率和进展的影响， 果蝇使用小分子、遗传-机械扰动和时间限制的进食和使用 人类整合多组学（NHLBI TopMed）。我们的项目将筛选出与治疗相关的基因， 失眠、睡眠和心血管疾病之间的联系。

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.