# A cross-species approach to hypersomnia genetics informed by human GWAS

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $489,263

## Abstract

Idiopathic hypersomnia (IH) is a poorly understood disorder characterized by excessive daytime
sleepiness despite normal nighttime sleep, often accompanied by difficulty awakening,
unrefreshing sleep, and cognitive impairment. Once thought to be present in <1% of the
population, recent work indicates a far greater prevalence, with underdiagnosis exacerbated by
a limited understanding of this disorder. IH patients commonly report poor management of
symptoms and impaired quality of life, and treatments are not based on disease etiology. Twin
studies show that daytime sleepiness is between 37-48% heritable and family history of
excessive sleepiness, IH, or other hypersomnia disorders is present in ~1/3 of IH patients.
Genome-wide association studies (GWAS) of hypersomnia traits have identified 24 genome-
wide significant SNPs specifically associated with increased sleep propensity. Here, we propose
a comprehensive approach to identify effector genes for hypersomnia-related traits, using
“variant to gene mapping to in vivo validation” that will intersect GWAS data with ATAC-seq and
high-resolution promoter- focused Capture C neuronal datasets derived from human induced
pluripotent stem cells (iPSCs) to identify potential effector genes. We will rapidly validate
identified candidates in an established Drosophila model of sleep and extend findings into
zebrafish to test for behavioral relevance in a vertebrate system. Using approaches described in
this proposal, we have already strongly implicated a gene, vertebrate CADM2, as associated
with hypersomnia-like phenotypes across species with loss of function. In Aim 1, we will use a
comprehensive combination of TAD-wise analysis of genome wide significant sleep propensity
loci and “3D Genomics” approaches in key cell types to implicate additional candidate effector
genes harbored in the sub-threshold P-value zones of the existing GWAS datasets. In Aim 2,
we will use Drosophila to determine the mechanism through which loss of CADM2 (functional
homolog in fly, beat-Ia) affects the function of key arousal circuits in the brain. In parallel, we will
screen identified candidate genes for relevance to excessive sleepiness in vivo in flies using an
RNAi-based approach. In Aim 3, we will rigorously examine sleep phenotypes in Cadm2b
knockout zebrafish and prioritize other candidate genes for vertebrate using a rapid CRISPR
approach pipeline. This project will identify novel genetic variants and the corresponding effector
genes that contribute to hypersomnia-related traits, thereby shedding light on the biological
pathways that influence the development of the traits. Study results will have fundamental
implications for novel approaches to the diagnosis, prevention, and treatment of IH.

## Key facts

- **NIH application ID:** 10981595
- **Project number:** 1R01NS135075-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Alessandra Chesi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $489,263
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981595

## Citation

> US National Institutes of Health, RePORTER application 10981595, A cross-species approach to hypersomnia genetics informed by human GWAS (1R01NS135075-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10981595. Licensed CC0.

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