# Genetic Architecture of Tinnitus and its Relationship to Hearing Loss

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

## Abstract

Tinnitus and hearing loss have been the #1 and #2 disabilities at the VA since
2006. Costs to the VA in excess of billions of dollars in disability payments include
health care visits, cost of hearing aids, and remedial therapies, including cognitive
behavioral therapy. Personal cost to the Veteran involves loss of employability, lost
productivity at work, reduced quality of life, as well as sleep difficulties and diminished
cognition. One reason that no effective treatment has been identified may be the large
heterogeneity in the Veteran population with respect to etiology, exposures, genetics,
and clinical phenotype.
 Our group published the first large genome-wide-association study (GWAS) for
tinnitus), identifying genomic variants and establishing tinnitus as a heritable, polygenic
disorder. We have curated the largest collection of data of tinnitus and hearing-related
phenotypes, comprising diverse populations with a wide range of acoustic exposure,
age, and ancestry. We now wish to continue this highly productive project to increase
gene discovery and further dissect the genomic landscape of tinnitus and hearing loss.
Specifically, the divergent anatomic and genomic pathways for tinnitus from hearing
damage remains unidentified.
 In Aim I we propose to expand and refine phenotyping for tinnitus using more
stringent criteria than self-report, i.e., disability ratings and clinical diagnoses. For the
first time in a large GWAS, we will use objective measures of hearing based on >
350,000 audiograms in MVP such as principal components and a speech intelligibility
index (SII). We will characterize exposure measures, comorbid disorders associated
with tinnitus, risk factors, and covariates for multi-trait GWAS. Aim 2 will use our
established pipeline to perform GWAS, including meta-analysis on MVP and UKB with
replication in external cohorts. In addition, we will optimize the contribution of diverse
ancestries to identify causal variants and ensure that our understanding of auditory
genetics extends across ancestries represented in MVP. We will identify tinnitus
subtypes using the multi-trait analysis from Aim 1. In Aim 3, we will perform post-GWAS
functional analysis including transcriptomic imputation association (TWAS) to predict
transcriptomic variation in relevant brain and cochlear tissues. In Aim 4, we will dissect
the shared and distinct genetic underpinnings of tinnitus, hearing loss, and loss of
speech intelligibility to improve risk prediction. We Will analyze genetic correlations of
auditory phenotypes with other disorders. In addition, we will evaluate polygenic risk
scores (PRS) to better predict risk of tinnitus clinically.
 Successful completion of these aims will identify relevant variants, genes, and
pathways, advance our knowledge of the genetic basis of tinnitus, dissect its relationship
to hearing loss, and expand findings to diverse populations exposed to a range of
environmental acoustic trauma. Our findings will provide a ...

## Key facts

- **NIH application ID:** 10656407
- **Project number:** 5I01BX005920-02
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Caroline M Nievergelt
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656407

## Citation

> US National Institutes of Health, RePORTER application 10656407, Genetic Architecture of Tinnitus and its Relationship to Hearing Loss (5I01BX005920-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10656407. Licensed CC0.

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