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

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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 susceptibility to tinnitus. Diverse genomic profiles may lead to tinnitus when triggered by environmental stimuli, such as noise, blast, or head trauma. On the other hand, for those who sustain tinnitus as a result of age, there may be other genetic factors involved. To date, studies have been too small to dissect out genes associated with the different etiologies. The MVP cohort provides the power to separate tinnitus into etiologies in order to identify separate phenotypes. !