Multi-ancestry GWAS of age-related hearing loss identifies 140 loci and key cellular mechanisms

Age-related hearing loss is a prevalent and growing public health issue among the elderly. Here, we perform a multi-ancestry genome-wide association study comprising 456,613 cases and 1,053,834 controls, identifying 140 independent loci associated with age-related hearing loss, including 44 novel signals. We further fine-map 9 likely causal missense variants for age-related hearing loss and provide evidence of purifying selection for age-related hearing loss-associated variants. Notably, genetic risk for age-related hearing loss is strongly correlated with behavior traits such as neuroticism score and irritability. Integration of molecular phenotypes identifies 22 genes and 85 DNA methylation sites significantly associated with age-related hearing loss. Moreover, analyses incorporating spatial and single-cell transcriptomic identify the inner ear as a crucial site of age-related hearing loss, emphasizing the importance of hair cells, supporting cells, basal and root cells of the stria vascularis to its pathogenesis. Our study provides genetic and cellular insights into age-related hearing loss and advance our understanding of its genetics architecture.