PROJECT SUMMARY/ABSTRACT Age-related hearing loss (presbyacusis) is among the most common chronic conditions of aging worldwide, is increasing at an alarming rate along with the older population, and constitutes a significant and costly public health concern. Genetic factors are among its many etiologies and the high prevalence of age- related hearing loss suggests that several fairly common alleles may play a significant role in its development and progression. Alternatively, age-related hearing loss could result from one or more mutations in a single gene. Recent work from the P50 Clinical Research Center (Experimental and Clinical Studies of Presbyacusis) and others strongly suggests that both mechanisms are involved. However, no genetic risk factor has yet been unequivocally identified and the lack of such information has impeded the development of screening assays to identify individuals who are at high risk or require protection. Thus, in Project 1 of our Parent P50 Clinical Research Center, a population-based cohort molecular genetic study was launched, taking advantage of whole exome sequencing to provide information about genetic contributions to age-related hearing loss in general, as well as to specific pathophysiologic phenotypes and biological pathways, thereby enabling the potential application of existing treatments and development of new treatments. Comprehensive bioinformatic analysis of exome sequence data from 532 well-characterized human subjects ≥55 years of age of non-Finnish European (NFE) ancestry, selected from MUSC’s unique longitudinal database, has now identified a substantial number of both common and rare variants as strong candidate genes for presbyacusis. In this Administrative Supplement, Aim 1 will expand the search for genes with a high variant load in hearing loss to include all participants in the NIH All of Us Research Program who have sequence data and to subgroups selected by race/ethnicity and sex using procedures for analysis of human subjects developed during studies of our Parent Center cohort and the UK Biobank. Aim 2 will investigate the same set of variants as in Aim 1 using a novel algorithm devised and used for the Parent Center cohort to determine if specific individual variants are linked to poorer or better pure-tone thresholds as compared to the age- and sex-matched non- carrier cohort. It is hoped that the increased sample size afforded by the NIH All of Us database will provide a means to undertake pathway enrichment studies that may lead to the identification of a broad range of target options at which to direct therapeutics aimed at preventing or slowing the progression of presbyacusis. Moreover, knowledge gained from this much larger and more inclusive study population about the distribution of specific variants between males and females and among older adults from different racial/ethnic backgrounds will facilitate precision medicine approaches for the selection of interventions for the ...