Population-genetic and evolutionary context of a CRIP3 variant associated with age-related hearing loss

Age-related hearing loss is a widespread sensory impairment affecting one third of the elderly population, yet the genetic underpinnings of this condition remain incompletely understood. In this study, we investigate the evolutionary context of a non-synonymous variant (rs2242416) in the CRIP3 gene, which is expressed in auditory hair cells, and previously associated with hearing loss. We first confirm that rs2242416 shows strong and consistent association with hearing loss across multiple genome-wide association studies. Notably, rs2242416 is also associated with reduced risk of heart related phenotypes, suggesting potential pleiotropic effects. The variant substitutes the nonpolar isoleucine for the polar threonine at an amino acid site that is otherwise highly conserved across placental mammals. By causing the amino acid change, the variant is predicted to subtly alter the structure of the CRIP3 protein. Moreover, the population genetics of the CRIP3 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 natural selection in generating this increased allele frequency in Eurasians remains inconclusive. Together, these results provide phenotypic, evolutionary, and molecular context for CRIP3 variation and highlight rs2242416 as a promising candidate for functional studies.Significance Statement Age-related hearing loss is highly prevalent, yet the specific genetic variants that contribute to disease risk remain poorly understood. Here, we investigate a variant (rs2242416) that causes an amino acid change in the CRIP3 gene. While this variant is associated with hearing loss in multiple genome-wide association studies (GWAS), virtually no focused attention has been given to it. By integrating GWAS findings with evolutionary and population genetic analyses, we provide broader context for interpreting this variant. Our results support rs2242416 as a candidate functional variant increasing hearing loss risk in humans. Overall, this study demonstrates the value of combining population genetics with human GWAS to prioritize variants for functional validation.