Innovative approaches to elucidate the etiology of age-related hearing loss and tinnitus in diverse populations

SUMMARY Age-related (AR) hearing loss (HL) is one of the most common conditions affecting adults. Tinnitus (i.e., ringing in the ears) and HL are often comorbidities, ARHL and tinnitus have several comorbidities that include Alzheimer’s disease/dementia, anxiety, asthma, cardiovascular disease, depression, diabetes (type 2), hypertension, obesity, sleep disorders, and stroke. A number of genes have been implicated in the etiology of ARHL/tinnitus through genome-wide and exome association studies that were conducted in predominantly white Europeans. Whole-genome sequence (WGS) data is now available on Europeans and non-Europeans, e.g., All of Us (AoU) (N=~409,000) and UK Biobank (UKB) (N=~500,000), but there is a lack of ancestry specific methods to analyze rare variants in admixed populations. To tackle this problem, we will develop Tractor-rare variant aggregate (RVA) and apply it to admixed populations in our study, i.e. individuals of African ancestry and Latinos. Tractor-RVA should provide better control of type I errors, increase power to detect associations, and allow for the estimation of ancestry specific effect sizes. The Tractor-RVA software and documentation will be made publicly available via CRAN and GitHub so it can be used by researchers to study other complex traits in admixed populations. The availability of WGS data should provide new associations for ARHL and tinnitus particularly for structural and rare variants, some which will be ancestry specific. To investigate the etiology of ARHL/tinnitus and their comorbidities we will analyze individuals of African, East Asian, European, Latino, and South Asian ancestry utilizing for following datasets: National Health and Nutrition Examination Survey (NHANES) (N=108,182), the National Health and Ageing Trends (NHATS) (N=8,245), and the National Health Interview Survey (NHIS) (N=357,714), as well as AoU and UKB. Additionally, to provide further clues into the etiology of ARHL/tinnitus we will evaluate the relationships between comorbidities and ARHL/tinnitus using two-sample bidirectional and multivariate Mendelian Randomization to better understand pathways. This study should facilitate a better understanding of the etiology of ARHL/tinnitus; aid in diagnosis and intervention strategies; and help to reduce health care disparities.