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Hearing loss is a major public problem with a heritability of up to 70%. Catechol-O-methyltransferase (COMT) encodes an enzyme that is highly expressed in sensory hair cells of the inner ear. The association between <i>COMT</i> and hearing loss has not been reported previously in nationally representative population-based studies. A regression linear model was used to estimate associations between the allele/genotype of <i>COMT</i> and self-reported hearing loss based on 13,403 individuals from Wave IV of the Add Health study, a nationally representative sample of multiethnic U.S. young adults. The inverse variance-weighted effect magnitude was estimated using a genetic meta-analysis model. The “A” allele frequency of rs6480 (a missense variant in <i>COMT</i>) was 0.44. The prevalence of hearing loss was 7.9% for individuals with the “A” allele and 6.5% for those with the “G” allele. The “A” allele was significantly associated with increased hearing loss (<i>p</i> = 0.01). The prevalence of hearing loss was 6.0%, 7.2%, and 8.7% for individuals with GG, AG, and AA genotypes, respectively, which was consistent with a genetic additive model. The genotypic association model showed that rs4680 was significantly associated with increased hearing loss (<i>p</i> = 0.006). A missense variant of rs4680 in <i>COMT</i> was significantly associated with increased hearing loss among young adults in a multi-racial/ethnic U.S. population-based cohort.