Genetics of age‐related hearing loss

Abstract

Age‐related hearing loss (ARHL) has recently been confirmed as a common complex trait, that is, it is heritable with many genetic variants each contributing a small amount of risk, as well as environmental determinants. Historically, attempts to identify the genetic variants underlying the ARHL have been of limited success, relying on the selection of candidate genes based on the limited knowledge of the pathophysiology of the condition, and linkage studies in samples comprising related individuals. More recently genome‐wide association studies have been performed, but these require very large samples having consistent and reliable phenotyping for hearing loss (HL), and early attempts suffered from lack of reliable replication of their findings. Replicated variants shown associated with ARHL include those lying in genes GRM7, ISG20, TRIOBP, ILDR1, and EYA4. The availability of large biobanks and the development of collaborative consortia have led to a breakthrough over the last couple of years, and many new genetic variants associated with ARHL are becoming available, through the analysis publicly available bioresources and electronic health records. These findings along with immunohistochemistry and mouse models of HL look set to help disentangle the genetic architecture of ARHL, and highlight the need for standardization of phenotyping methods to facilitate data sharing and collaboration across research networks.

The Genetic contribution to solving the cocktail-party problem

“…By contrast, age-related sensorineural hearing loss (ARSHL) is extremely common, affecting around 40% of adults over 60 years old ( Hoffman et al., 2017 ). Our understanding of the genetics of ARSHL lags behind that of prelingual hearing loss ( Wells et al., 2020 ). Prior family studies have shown that HTs are heritable, or correlated among biological relatives, suggesting that there is a sizable genetic component to ARSHL ( Duan et al., 2019 ; Hendrickx et al., 2013 ; Kvestad et al., 2012 ; Raynor et al., 2009 ).…”

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

“…The contribution of EYA4 variants to hearing loss has been well established. 55 HOMER2 is involved in intracellular homeostasis of calcium and cytoskeletal organization and has been previously associated with hearing loss, 56 but its function within the stria vascularis remains unknown. TMPRSS9 encodes a membrane-bound serine polyprotease involved in the proliferation of inner ear progenitor cells in the mouse cochlea.…”

Perspectives on Human Hearing Loss, Cochlear Regeneration, and the Potential for Hearing Restoration Therapies

“…For families with hearing loss variants, knowing the specific sequences underlying their hearing loss allows medical providers to predict if their hearing loss is part of a syndrome that may lead to further comorbidities, including heart [ 19 ], thyroid [ 20 ], or visual dysfunction [ 21 ]. Genetic variants may also potentiate hearing loss from noise damage [ 22 ], drug damage [ 23 ], or aging [ 24 ]. It is important to note that even within families, the same genetic variants can lead to hearing loss on different time scales and to differing extents, likely due to the presence of genetic or environmental modifiers.…”