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Understanding the genetic underpinnings of disabling hearing loss, which affects [~]466 million people worldwide, can provide avenues for new therapeutic target development. We performed a genome-wide association meta-analysis of hearing loss with 125,749 cases and 469,497 controls across five cohorts, including UK Biobank, Geisinger DiscovEHR, the Malmo Diet and Cancer Study, Mount Sinais BioMe Personalized Medicine Cohort, and FinnGen. We identified 53 loci affecting hearing loss risk, 18 of which are novel, including coding variants in COL9A3 and TMPRSS3. Through exome-sequencing of 108,415 cases and 329,581 controls from the same cohorts, we identified an association with rare predicted loss-of-function variants in a gene that has been uncharacterized in hearing loss, KLHDC7B (odds ratio [OR] = 2.14, P = 5.2 x 10-30), and with coding variants in two genes previously implicated in animal models of hearing loss (SYNJ2, OR = 1.31, P = 1.3 x 10-14; FSCN2, OR = 1.24, P = 4.1 x 10-15). We also observed single-variant and gene-burden associations with 11 genes known to cause Mendelian forms of hearing loss, including an increased risk in heterozygous carriers of mutations in the autosomal recessive hearing loss genes GJB2 (Gly12fs; OR = 1.21, P = 4.2 x 10-11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 x 10-17). Our results show that Mendelian hearing loss genes contribute to the burden of hearing loss in the adult population, and suggest a shared etiology between common and rare forms of hearing loss. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common traits in which risk is modulated by both common and rare variation.

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