# Genome-wide association study of tinnitus in the Million Veterans Program with emphasis on traumatic brain injury

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2021 · —

## Abstract

SUMMARY/ABSTRACT
 The goals of this study are to characterize a phenotype for tinnitus in a Veteran population
and to identify genes and gene-by-environment (GxE) interactions that predict development of
tinnitus. Tinnitus, or ringing in the ears with no external source, has been the #1 disability
compensation diagnosis at the VA since 2006 and is reported in over 30% of the current MVP
population. Besides disability payments, costs to the VA include treatment for its comorbidities,
including depression and anxiety disorders, sleep deprivation, suicidal association, cognitive
disorders, post-traumatic stress syndrome, and hearing loss, comprising audiologic visits and
costs of hearing aids. Yet, to date, there is no objective phenotype, objective biomarker, or
definitive treatment associated with this disorder.
 Although highly correlated with hearing loss, secondary to age, noise, and traumatic brain
injury (TBI), tinnitus is a separate and distinct symptom, and a preponderance of evidence
indicates that tinnitus is elicited in the brain. Concomitantly, the cochlea is the source of hearing
loss, and tinnitus and hearing loss will thus have separate genetic architecture. To date, there
have been no genome-wide association studies (GWAS) large enough to separate genes
associated with these different etiologies, nor to indicate why some people sustain tinnitus and
some do not. The current MVP cohort of over 350,000 Veterans has sufficient power to aid in
genetic delineation of disparate etiologies of tinnitus, including age, traumatic brain injury, blast,
and noise-induced tinnitus.
 Suggestions for candidate genes have included pathways involved with oxidative stress,
inflammation, potassium-channel receptors, and nerve repair, among others. However, all of
these studies were performed in small cohorts with less than adequate power. Our GWAS on the
active-duty Marine Resiliency Study (MRS) cohort of average age 22 suggests several genes
expressed in the brain that are involved in axonal growth in development and neural repair
correlated to TBI. On the other hand, MVP contains over 107,000 subjects with self-reported
tinnitus of average age 68, and our Vietnam Era Twin Study on Aging (VETSA) averages 55
years of age. These different cohorts with tinnitus, hearing, and environmental exposure data will
allow separation of age-related from noise-induced and TBI-related tinnitus. Distinct phenotypes
will be determined by self-report, electronic health record data, and standardized patterns of
audiogram data.
 Our heritability studies on VETSA data indicate a gene by environment interaction (GxE)
including a liability threshold model rather than a model that postulates additive genetic factors, in
agreement with other studies. Utilizing the power of a twin study, there is evidence for a threshold
of injury beyond which susceptible individuals will incur tinnitus.
 The study's overarching hypothesis is that different genomic variations give rise to
susce...

## Key facts

- **NIH application ID:** 10247446
- **Project number:** 5I01RX002744-03
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Allen F. Ryan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247446

## Citation

> US National Institutes of Health, RePORTER application 10247446, Genome-wide association study of tinnitus in the Million Veterans Program with emphasis on traumatic brain injury (5I01RX002744-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10247446. Licensed CC0.

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