Age-related hearing loss is a consequence of accumulated environmental stresses to the cochlea and an intrinsic genetically-controlled aging process, with as much as 60% of hearing losses in the elderly being attributable to heritability. The often uncertain medical and noise histories in human subjects coupled with the high variability in the age of onset, rate of progression and the nature and severity of the hearing impairments make it difficult to attribute presbyacusis to a specific cause. Moreover, this phenotypic variability and other characteristics strongly suggest that age-related hearing loss is a complex polygenic disorder possibly involving different alleles on multiple genes. Recent advances in next generation sequencing have provided a powerful new tool to address the genetic basis of many age-related diseases. Here we propose to investigate the genetic and molecular basis of human presbyacusis. This project takes advantage of our extensive and continuously growing database containing well documented medical, noise and auditory function histories along with DNA samples from large numbers of human subjects. It also capitalizes on the development of new algorithms based on audiograms and data from animal models to define specific age-related hearing loss phenotypes in our experimental subjects. Accordingly, we propose to perform a comprehensive population-based cohort molecular genetic study to provide information about genetic contributions to specific phenotypes and biological pathways involved with age-related hearing loss.
Aim 3. 1 recruits additional subjects to increase the size of our discovery and replication cohorts.
Aim 3. 2 identifies genetic variants associated with increased susceptibility to presbyacusis employing genome-wide association analysis using whole exome sequence data.
Aim 3. 3 determines the pathological and potential functional consequences of genetic variants causing age-related hearing loss by assessing the distribution and changes in the expression pattern of promising candidate gene products and their association with pathological changes in human temporal bones.

Public Health Relevance

Although it is estimated that over 60% of age-related hearing loss can be attributed to genetics, no causative genetic variants or mutations in genes have so far been unequivocally identified. The identification ofthe structural variations in genes that cause specific forms of age-related hearing loss is an essential first step in the development of new diagnostic tests and the discovery of new drugs for the prevention and treatment of this common public health issue.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Specialized Center (P50)
Project #
2P50DC000422-26
Application #
8628450
Study Section
Special Emphasis Panel (ZDC1-SRB-K (15))
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
26
Fiscal Year
2014
Total Cost
$298,001
Indirect Cost
$77,854
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Lewis, Morag A; Nolan, Lisa S; Cadge, Barbara A et al. (2018) Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes. BMC Med Genomics 11:77
Bologna, William J; Vaden Jr, Kenneth I; Ahlstrom, Jayne B et al. (2018) Age effects on perceptual organization of speech: Contributions of glimpsing, phonemic restoration, and speech segregation. J Acoust Soc Am 144:267
Panganiban, Clarisse H; Barth, Jeremy L; Darbelli, Lama et al. (2018) Noise-induced dysregulation of Quaking RNA binding proteins contributes to auditory nerve demyelination and hearing loss. J Neurosci :
Chiarello, Christine; Vaden Jr, Kenneth I; Eckert, Mark A (2018) Orthographic influence on spoken word identification: Behavioral and fMRI evidence. Neuropsychologia 111:103-111
Harris, Kelly C; Vaden Jr, Kenneth I; McClaskey, Carolyn M et al. (2018) Complementary metrics of human auditory nerve function derived from compound action potentials. J Neurophysiol 119:1019-1028
McRackan, Theodore R; Fabie, Joshua E; Burton, Jane A et al. (2018) Earphone and Aided Word Recognition Differences in Cochlear Implant Candidates. Otol Neurotol 39:e543-e549
Dubno, Judy R (2018) Beyond the audiogram: application of models of auditory fitness for duty to assess communication in the real world. Int J Audiol 57:321-322
McRackan, Theodore R; Clinkscales, William B; Ahlstrom, Jayne B et al. (2018) Factors associated with benefit of active middle ear implants compared to conventional hearing aids. Laryngoscope 128:2133-2138
Dias, James W; McClaskey, Carolyn M; Harris, Kelly C (2018) Time-Compressed Speech Identification Is Predicted by Auditory Neural Processing, Perceptuomotor Speed, and Executive Functioning in Younger and Older Listeners. J Assoc Res Otolaryngol :
Worley, Mitchell L; Schlosser, Rodney J; Soler, Zachary M et al. (2018) Age-related differences in olfactory cleft volume in adults: A computational volumetric study. Laryngoscope :

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