title: 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.
authors.affiliation: Graduate Program in Surgical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Lavinsky
authors.affiliation: Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Crow
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Calvin
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Juemei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Ksenia A
authors.initials: KA
authors.lastname: Aaron
authors.affiliation: Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Ho
authors.affiliation: Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Pehzman
authors.initials: P
authors.lastname: Salehide
authors.affiliation: Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Myint
authors.affiliation: Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Maya
authors.initials: M
authors.lastname: Monges-Hernadez
authors.affiliation: Department of Computer Science, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Eleazar
authors.initials: E
authors.lastname: Eskin
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.affiliation: Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Otolaryngology, Zilkha Neurogenetic Institute, USC Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Rick A
authors.initials: RA
authors.lastname: Friedman
mesh_terms: D000818:Animals; D005072:Evoked Potentials, Auditory; D055106:Genome-Wide Association Study; D006317:Hearing Loss, Noise-Induced / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019255:NADPH Oxidases / Q000235:genetics*
chemical_list: D019255:NADPH Oxidases; C484511:Nox3 protein, mouse