Genetic and functional evidence implicates a <i>CRIP3</i> non-synonymous variant in age-related hearing loss

Age-related hearing loss is a widespread sensory impairment affecting a significant proportion of the elderly population, yet the genetic underpinnings of this condition remain incompletely understood. In this study, we investigate a non-synonymous variant (rs2242416) in the <i>CRIP3</i> gene, which is expressed in auditory hair cells, in the context of hearing loss. Firstly, we find the variant shows strong and consistent association with hearing loss across multiple genome-wide association studies. Secondly, this variant, substitutes the nonpolar isoleucine for the polar threonine at an amino acid site that is otherwise highly conserved across placental mammals. Thirdly, by causing the amino acid change, the variant subtly alters the structure of the CRIP3 protein. Together, these three analyses provide phenotypic, evolutionary, and molecular evidence for the functionality of <i>CRIP3</i> and its role in hearing loss. Moreover, the population genetics of the <i>CRIP3</i> locus reveals an increased frequency of the derived threonine allele of rs2242416 in Eurasian populations following the out-of-Africa migration of humans more than 50,000 years ago. Nevertheless, the role of Darwinian selection in this increased frequency remains inconclusive. Overall, our results make a compelling argument to auditory researchers to make a <i>CRIP3</i> mouse model to pinpoint the precise role of the protein in auditory function. Such a model will pave the way for therapeutic interventions targeting the CRIP3 protein to mitigate age-related hearing loss.