A Multi-omics Investigation of Incident Persistent Tinnitus

ABSTRACT Over 50 million Americans experience tinnitus. Persistent tinnitus can cause considerable suffering and disability, impairing sleep, cognition, mental health and daily function, and the economic burden due to disability, lost productivity and healthcare costs is substantial. However, little is known about the precipitants

and pathways that lead to persistent tinnitus and treatment options are limited. Our long-term goal is to identify treatment targets and preventative strategies to reduce tinnitus burden and improve quality of life. Our overall objectives are to (i) identify novel metabolomic and multi-omic risk factors for the development of tinnitus

among two large longitudinal cohorts of women (N>26,000); and (ii) collect tinnitus-related individual level data in two additional ongoing cohorts of younger and more diverse men and women (N>70,000). Our central hypotheses are that specific plasma metabolites are associated with risk of developing tinnitus and that genetic

variants influence how environmental exposures contribute to the development of tinnitus. The rationale is that identifying risk factors for tinnitus will provide a strong scientific framework for improving tinnitus management, and expanding data collection to include younger individuals will create a comprehensive resource that will

enable studies of genetic and environmental factors and will be invaluable in advancing future tinnitus research. The study objectives will be addressed in three specific aims: 1) Identify plasma metabolomic risk factors for developing persistent tinnitus; 2) Evaluate genomics and gene-environment interactions as risk

factors for developing persistent tinnitus; and 3) Collect tinnitus information in two ongoing cohorts of younger individuals. We will leverage rich assets from four longitudinal cohort studies and findings from two large tinnitus genome-wide association studies (GWAS). In Aim 1, we will use logistic regression to identify novel

metabolomic risk factors for developing tinnitus. In Aim 2a, we will conduct a GWAS and perform a meta- analysis with published tinnitus GWAS results from the UK Biobank. In Aim 2b, we will assess how genetic variations in enzymes responsible for caffeine and analgesic metabolism modulate associations between

caffeine intake or analgesic use and tinnitus risk. In Aim 3, we will leverage regularly administered questionnaires in 2 well-characterized younger cohorts to collect detailed tinnitus information. This innovative proposal integrates omics with epidemiological data to identify new risk factors for tinnitus, improve

understanding of tinnitus etiology and reveal metabolic pathways and candidate genes for future functional follow-up. The proposed research is significant because identifying risk factors and omics precursors may enable earlier neuroprotective interventions when treatments are more likely to be effective. As an early-stage

investigator, this project will provide me with necessary preliminary data for a future R01 proposal to extend these large-scale multi-omics investigations of tinnitus, identify additional novel risk factors, and uncover new treatment targets in women and men across the lifespan, and advance my career to the next stage.