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: 10621177
• 负责人: Girish C. Melkani
• 金额: $ 74.98万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621177
• 关键词: 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; Maps; Mechanics; Mendelian randomization; Modeling; Mus; National Heart, Lung, and Blood Institute; Orthologous Gene; Outcome; Participant; Pathway Analysis; Pathway interactions; Patient Self-Report; Persons; 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; 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; improvement on sleep; knock-down; loss of function; metabolomics; model organism; 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.

项目摘要/摘要 失眠症发生在10-20％的人口中，并赋予了> 2倍的因果关系风险 心血管疾病（CVD）基于我们最近的孟德尔随机研究。识别新的治疗 减轻CVD风险的失眠目标，剖析失眠的因果病理学很重要 并区分CVD的增加是由共同的因果机制还是特定的心血管 失眠状态引起的侮辱。该建议是由研究问题激发的：失眠是如何 导致CVD增加，以及应针对预防或延迟CVD的哪些特定机制？ 我们发现了57个全基因组显着的遗传基因座，用于失眠，并与CVD建立了稳健的因果关系， 但是需要改善对特定共享因果途径和机械链接的理解以移动 采用个性化的有效疗法。最近的模型生物研究描述了特定机械链接 在睡眠，免疫力，动脉粥样硬化和心血管疾病之间，我们也可以测试疾病相关性 在人们破译收敛机制中。因此，在这里我们建议利用基因组测序和 来自英国生物库的多族类样品中的多民族样本中的综合多媒体，重点是 果蝇中睡眠和心血管功能的功能研究以找到因果基因并识别 有因果关系将失眠与CVD联系起来的机制。我们提出以下特定目的：1）查找因果关系 57个基因建立了失眠的遗传基因座，并剖析了潜在的疾病机制和途径 人类（NHLBI顶级和英国生物库）。多民族精细映射和稀有变体分析将确定 由多特征关联告知的因果基因和软聚类分析将确定异质 失眠机制和亚型。 2）测试果蝇功能丧失的结果 有关睡眠和心血管功能的因果人失眠基因的直系同源物。表型效应和基因 表达模式将被系统地表征以解开重要的功能途径和网络。 3）测试扰动睡眠（破坏或改善）对CVD发病率和进展的影响 果蝇使用小分子 - 遗传机械扰动和时间限制的进食和使用 人类中的综合多媒体（NHLBI顶部）。我们的项目将在治疗中列出与治疗相关的基因和 连接失眠，睡眠和CVD的途径。

项目成果

Genetic evidence for a potential causal relationship between insomnia symptoms and suicidal behavior: a Mendelian randomization study.

• DOI: 10.1038/s41386-022-01319-z
• 发表时间: 2022-08
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 影响因子: 7.6
• 作者: Nassan, Malik;Daghlas, Iyas;Winkelman, John W.;Dashti, Hassan S.;Saxena, Richa
• 通讯作者: Saxena, Richa