Project Summary / Abstract
Age-related hearing impairment (ARHI) is the most common cause of hearing loss, is heritable, and is one
of the most prevalent conditions affecting the elderly globally. Twin and family studies reveal 25-75%
heritability for ARHI (Momi et al., 2015). Estimates suggest approximately two‐thirds of people over the age of
70 in the United States experience ARHI, and that by 2020, over half of all people in the United States with
hearing loss will be over 70 years of age (Bainbridge and Wallhagen, 2014). ARHI has been shown to be
independently associated with cognitive decline, dementia, depression, and loneliness and results in an
estimated annual economic burden of over $3 billion (Deal et al., 2017; Deal et al., 2018; Lin and Albert, 2014).
Our overarching hypothesis, supported by preliminary data in both mice and humans, is that ARHI is a
complex trait with many likely genes associated (Fransen et al., 2015; Friedman et al., 2009; Kalra et al., 2019;
Wells et al., 2019). Greater than 100 genes have been identified for monogenic deafness; however, a
substantial fraction of patients with ARHI have no identifiable mutation in any known deafness gene suggesting
that there remain additional genes to discover (Bowl and Dawson, 2018).
Mice continue to be the predominant organism for hearing research. Similarities in the auditory structure
and physiology between mice and humans, the close evolutionary relationship of genomes (most genes in
mice have a human homologue), relatively low housing costs, genetic standardization and the available
genetic toolkit make the mouse a crucial model system for the study of the functional genomics of the auditory
system (Bowl and Dawson, 2015). We are proposing to identify candidate genes by performing the first
complete genome-wide association study (GWAS) of ARHI in CFW mice and examining gene expression in
the inner ear. Although several labs including ours have used human subjects for GWAS, to date there exist no
comprehensively characterized cohorts with sufficient power and therefore there exist limited replication
studies of candidate genes. In Aim 1, we will measure auditory brainstem response and distortion product
otoacoustic emission thresholds in 2,000 one-year-old CFW mice equally divided among males and females.
We will genotype each mouse at more than 1,000,000 single nucleotide polymorphism markers and in Aim 2
perform GWAS to identify quantitative trait loci (QTL). In Aim 3, we will use RNAseq to assess differences in
gene expression in the inner ears of 100 randomly selected mice from the CFW cohort and define expressed
QTLs (eQTLs).The genetic variation within CFW mice presents a unique opportunity to elucidate the molecular
mechanisms that underlie ARHI providing novel targets for drug development and providing a means for
identifying patients at risk.