# The genetics of functional decline in the aging vestibular system: A GWAS and gene expression analysis in aging mice and humans

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $792,321

## Abstract

Fall-related injury in the elderly carries a 20% mortality rate, and is the sixth leading cause
of death in this population. Age-related dysfunction of gravity receptors within the vestibular
system is highly correlated with these elderly falls, and significant age-related degeneration is
associated with nearly all types of vestibular cells. The overarching goal of this study is to analyze
human and mice genome-wide association studies (GWAS), vestibular-specific human and mice
genomic expression, and single-cell sequencing of specific sites in the vestibular system, then
test identified genes and related pathways in the lab. Our objective is to characterize the genomics
related to age-related imbalance for future prevention and treatment. The central hypothesis is
that by this analysis, we can identify anatomic and physiologic sites relevant to the balance system
that is common to both species. Our rationale is that by this analysis, we can better focus on
relevant genes and pathways for lab testing and ultimate therapeutic intervention. Building upon
a small GWAS on elderly falls that correlated human DCC and PTK2 genes in the same pathway
as Dcc identified in the Hybrid Mouse Diversity Panel (HMDP) GWAS, our specific aims will be:
1) a. Perform GWAS in humans based on a dizziness/falls phenotype in a meta-analysis of large
datasets; b. GWAS in mice based on a behavioral and gravity sensor function phenotype in the
HMDP; 2) a. Perform RNA-Sequencing on vestibular tissues from mice and human surgical
specimens; b. Single-cell RNA-Seq on individual tissues; c. Compare identified genes and
pathways via computational methods to assess translation of pathways from the mouse to human
balance system; and 3) Perform functional testing for the top candidates defined in Aim 2 using
knock-out/knock-in mice. Multiple innovations of this project include: 1) the first GWAS of gravity
receptor function in aged mice and in elderly humans, 2) a comprehensive catalogue of genes
and pathways involved in vestibular functional variation with inter-species comparison, as part of
FAIR (findable, accessible, interoperable, reusable) Compliance, 3) in vivo validation in mouse
models and an analysis of these candidates in available human cohorts, and 4) future potential
for targeted therapies. Our outcome is the first comparative GWAS of the balance system
between animal models and humans. The impact of this work will be to lay a firm foundation for
development of targeted treatment of the balance system to diminish falls in the elderly.

## Key facts

- **NIH application ID:** 10867376
- **Project number:** 5R01DC020052-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Royce Ellen Clifford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $792,321
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867376

## Citation

> US National Institutes of Health, RePORTER application 10867376, The genetics of functional decline in the aging vestibular system: A GWAS and gene expression analysis in aging mice and humans (5R01DC020052-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10867376. Licensed CC0.

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