Genome-Wide Association Study Identifies Nox3 as a Critical Gene for Susceptibility to Noise-Induced Hearing Loss

Abstract

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.

Genetic and environmental control of host-gut microbiota interactions

“…Rather than using linkage analysis, as is traditional in mouse genetics, we employed association across the HMDP strains, since the resolution of mapping is one or two orders improved (Bennett et al 2010). Such association analysis has now been used to identify novel genes which were subsequently validated in a number of cases (Farber et al 2011;Lavinsky et al 2015;Parks et al 2015;Rau et al 2015), but given the structure of the inbred mouse population, there is some potential for long-range linkage disequilibrium. The proportion of each common taxon was treated as an individual trait, and association analyses were performed with 198,431 informative SNPs spaced throughout the mouse genome using a mixed-model algorithm that corrects for population structure (Kang et al 2008).…”

“…The resource has several advantages for genetic analysis as compared to traditional genetic crosses. First, it allows high-resolution mapping by association rather than linkage analysis, and it has now been used for the identification of a number of novel genes underlying complex traits (Farber et al 2011;Lavinsky et al 2015;Parks et al 2015;Rau et al 2015). Second, since the strains are permanent, the data from separate studies can be integrated, allowing the development of large, publicly available databases of physiological and molecular traits relevant to a variety of clinical disorders (systems.genetics.ucla.edu and phenome.jax.org).…”

Acquired Hearing Loss in Children

“…8 Genetic susceptibility is well documented for hearing loss related to aminoglycosides and may also be a factor in patients with noise-related hearing loss and ototoxicity related to other medications. 9 Although much of congenital or childhood-onset hearing loss is genetic, recessive, and nonsyndromic, audiometric evaluation of biological parents and siblings may document previously unsuspected hearing loss as well, making a genetic cause of what seems an acquired hearing loss more likely.…”

Large-scale phenotyping of noise-induced hearing loss in 100 strains of mice

“…In particular, the recombinant inbred strains, which include AXB, BXA, BXD, BXH, and CXB, are derived from pairwise crosses of classical inbred strains; their inclusion in the HMDP significantly increases the statistical power to detect single-nucleotide polymorphisms (SNPs) associated with complex traits [25]. We recently published a genome-wide association study utilizing the HMDP to identify NADPH oxidase3 ( Nox3 ) as a NIHL susceptibility gene [26]. In this manuscript, we present the complete 100 strain panel of baseline ABR threshold phenotypes and noise sensitivity phenotypes with the hope that this data will facilitate future investigations in hearing research.…”