# Dissecting Causal Role of Insomnia in Cardiovascular Disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $775,399

## Abstract

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.

## Key facts

- **NIH application ID:** 9974174
- **Project number:** 1R01HL146751-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Girish C. Melkani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $775,399
- **Award type:** 1
- **Project period:** 2020-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974174

## Citation

> US National Institutes of Health, RePORTER application 9974174, Dissecting Causal Role of Insomnia in Cardiovascular Disease (1R01HL146751-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9974174. Licensed CC0.

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