# Genomic effects of chronic neurotrauma on hearing loss; relationship between hearing loss, TBI, mild cognitive impairment, and dementia

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

World-wide, hearing loss and traumatic brain injury (TBI) are the top two risk factors for dementia in mid-
life. Together the two disorders account for approximately 11% of the potentially modifiable attributable risk
fraction for dementia. Chronic auditory sensory disorders including hearing damage and difficulties
understanding speech in noise complicate recovery even from mild TBI. In addition, comorbidities of
hearing difficulties include loss of employability, depression, difficulties with cognition, and suicide. The use of
hearing aids is associated with the delay of the onset of age-related dementia, and significant genetic overlap
exists between Alzheimer’s disease and hearing loss.
 A critical gap in our understanding consists of genetic vulnerabilities to hearing loss related to TBI. Using
the largest global genomic dataset with audiogram and TBI data, our overarching objective is to identify genetic
variants associated with hearing loss with and without the environmental incidence of TBI. The difference in TBI-
induced hearing loss and hearing difficulties secondary to aging and noise is indicated by anatomic studies that
demonstrate a central neurologic component with TBI in addition to peripheral cochlear damage. We propose to
perform the first large genomic studies with objective audiologic data, using over 1.2 million audiograms in
373,744 Veteran participants, in the largest study to date of a specific etiology for hearing impairment.
The study will include audiogram thresholds, speech psychometrics, and a measure of speech intelligibility in
noise to identify genetic variants, genes, and pathways associated with hearing difficulties secondary to TBI. We
will then assess a polygenic risk score (PRS) to predict those Veterans most at risk for dementia who might
benefit from early combined treatment, such as hearing augmentation and neurocognitive therapy.
 The first specific aim will establish criteria on multiple phenotypes for hearing loss. We have aggregated
audiogram data from the VA and DoD medical record to calculate pure-tone averages, principal components,
and a measure of individual deviation from a predicted speech intelligibility index. We will then characterize TBI,
mild cognitive impairment, and dementia according to self-report on MVP questionnaires and diagnoses in the
electronic health record. In the second aim, we will conduct separate GWAS in individuals of diverse ancestries
represented in the US military using multiple phenotypes, subsequently adding TBI as a Gene x Environment
variable. Analysis of variants and genes identified will consist of functional annotation, including correlations with
other disorders and traits, categorizing relevant molecular pathways, and incorporating transcription information
from the cochlea and brain to focus our results to genes relevant to hearing impairment. An exploratory aim will
formulate and test a polygenic risk score for hearing loss following TBI. A predictive model fo...

## Key facts

- **NIH application ID:** 10536525
- **Project number:** 1I01RX004293-01
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Royce Ellen Clifford
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536525

## Citation

> US National Institutes of Health, RePORTER application 10536525, Genomic effects of chronic neurotrauma on hearing loss; relationship between hearing loss, TBI, mild cognitive impairment, and dementia (1I01RX004293-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536525. Licensed CC0.

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