In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL) of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP) to a 10 kHz octave band noise at 108 dB for 2 hours and assessed the permanent threshold shift 2 weeks post exposure using frequency specific stimuli. These data were then used in a genome-wide association study (GWAS) using the Efficient Mixed Model Analysis (EMMA) to control for population structure. In this manuscript we describe our GWAS, with an emphasis on a significant peak for susceptibility to NIHL on chromosome 17 within a haplotype block containing NADPH oxidase-3 ( Nox3 ). Our peak was detected after an 8 kHz tone burst stimulus. Nox3 mutants and heterozygotes were then tested to validate our GWAS. The mutants and heterozygotes demonstrated a greater susceptibility to NIHL specifically at 8 kHz both on measures of distortion product otoacoustic emissions (DPOAE) and on auditory brainstem response (ABR). We demonstrate that this sensitivity resides within the synaptic ribbons of the cochlea in the mutant animals specifically at 8 kHz. Our work is the first GWAS for NIHL in mice and elucidates the power of our approach to identify tonotopic genetic susceptibility to NIHL. Author Summary Noise-induced hearing loss (NIHL) is the most common work-related disease in the world and the second cause of hearing loss. Although several candidate gene association studies for NIHL in humans have been conducted, each are underpowered, un-replicated, and account for only a fraction of the genetic risk. Buoyed by the prospects and successes of human association studies, several groups have proposed mouse genome-wide association studies. The environment can be carefully controlled, facilitating the study of complex traits like NIHL. In this manuscript, we describe, for the first time, an association analysis with correction for population structure for the mapping of several loci for susceptibility to NIHL in inbred strains of mice. We identify Nox3 as the associated gene for susceptibility to NIHL that the genetic susceptibility is frequency specific and that it occurs at the level of the cochlear synaptic ribbon.
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