Dissecting Causal Role of Insomnia in Cardiovascular Disease

剖析失眠与心血管疾病的因果关系

• 批准号: 10159305
• 负责人: Girish C. Melkani
• 金额: $ 75.42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159305
• 关键词: Animal Model; Atherosclerosis; Behavior; Biological; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Clinical Trials; Cluster Analysis; Code; Coronary Arteriosclerosis; Data; Disease; Drosophila genus; Etiology; Functional disorder; Future; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic study; Genets; Goals; Heart Abnormalities; Hematopoiesis; Human; Human Genetics; Immunity; Incidence; Intervention; Knock-in; Lead; Life Style; Link; Mechanics; Mendelian randomization; Modeling; Mus; National Heart, Lung, and Blood Institute; Orthologous Gene; Outcome; Participant; Pathway Analysis; Pathway interactions; Patient Self-Report; Phenotype; Population; Proteomics; RNA Interference; Research; Risk; Role; Sampling; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Symptoms; Testing; Therapeutic; Time-restricted feeding; Tissues; Trans-Omics for Precision Medicine; Work; base; biobank; cardiovascular disorder risk; causal variant; cohort; cost efficient; design; effective therapy; exome sequencing; fly; genome sequencing; genome wide association study; genome-wide; genomic locus; human disease; improved; knock-down; loss of function; metabolomics; multi-ethnic; multiple omics; new therapeutic target; polygenic risk score; preclinical study; prevent; rare variant; small molecule; therapeutic evaluation; trait; transcriptomics

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.

项目概要/摘要 10-20% 的人口患有失眠症，导致事件的因果风险增加 2 倍以上 心血管疾病（CVD）基于我们最近的孟德尔随机研究。确定新的治疗方法 失眠的目标是改善心血管疾病风险，剖析失眠的因果病理生理学很重要 并区分 CVD 风险增加是否源于共同的因果机制或特定的心血管疾病 失眠状态引起的侮辱。该提案的动机是研究问题：失眠是如何发生的？ 导致CVD增加，应针对失眠的哪些具体机制来预防或延缓CVD？ 我们发现了 57 个全基因组显着的失眠遗传位点，并与 CVD 建立了强有力的因果关系， 但需要更好地理解特定的共享因果路径和机制联系，以便采取行动 走向个性化、有效的治疗。最近的模型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关系，我们也可以测试疾病的相关性 使人们能够破译趋同机制。因此，我们在这里建议利用基因组测序和 来自 TopMed 的多种族样本的综合多组学和英国生物银行的外显子组测序，重点关注 对果蝇睡眠和心血管功能的功能研究，寻找因果基因并确定 失眠与心血管疾病之间的因果关系机制。我们提出以下具体目标：1）查明因果关系 57个已建立的失眠基因位点的基因并剖析潜在的疾病机制和途径 人类（NHLBI TopMed 和英国生物银行）。多民族精细绘图和罕见变异分析将精确定位 由多性状关联提供的因果基因和软聚类分析将识别异质性 失眠疾病机制和亚型。 2) 测试果蝇功能丧失的后果 人类失眠基因对睡眠和心血管功能的直向同源物。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) 测试睡眠障碍（中断或改善）对 CVD 发病率和进展的影响 果蝇使用小分子、遗传机械扰动和限时喂养和使用 人类综合多组学（NHLBI TopMed）。我们的项目将列出与治疗相关的基因和 失眠、睡眠和心血管疾病之间的联系途径。