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 ...