NEW YORK – An international team led by investigators in Sweden, the UK, and the Netherlands has identified four dozen variants linked to hearing loss — a risk variant set highlighting the importance of a stria vascularis structure in the ear's cochlear duct wall.
"Taken together, these findings suggest that dysfunctions in the stria vascularis involve a large range of molecular mechanisms, globally impacting strial function," corresponding and co-senior author Christopher Cederroth, a physiology and pharmacology researcher affiliated with the Karolinska Institute, the University of Nottingham, and the Nottingham University Hospitals NHS Trust National Institute for Health Research, and his coauthors wrote in the American Journal of Human Genetics on Monday.
Starting from a genome-wide association analysis meta-analysis that included almost 723,300 adult individuals of European descent with or without clinically diagnosed or self-reported hearing loss from 17 prior hearing loss GWAS, the researchers focused in on 10 new and 38 known hearing loss-associated loci, including multiple missense variants falling at familial hearing loss-related loci or in genes flagged by gene set enrichment analyses.
"The present genome-wide meta-analysis is among the largest conducted in hearing genetics to date and provides an association catalog that helps to refine the fundamental basis of hearing loss," the authors wrote.
"The results provide a valuable resource for the selection of promising genes for further functional validation in pre-clinical models and define targets for screening purposes, drug development, gene therapy, or stratification approaches," they explained. "We believe such experiments will serve as a solid foundation for ultimately improving therapies against hearing loss."
With follow-up analyses on variants implicated in hearing loss — including analyses on new or previously published 10x Genomics single-cell RNA sequence or single-nucleus RNA-seq profiles on samples from the mouse brain and cochlea — the team saw signs that the risk variant set affected cell types found in the stria vascularis of the cochlea, but did not appear to hinge on alterations affecting cells in the brain.
The risk variant set also pointed to the apparent importance of sensory hair cell-related processes such as cytoskeleton organization and actin binding activity, the researchers reported, though they did not see a significant enrichment of risk variants in genes linked more broadly to cells in an ear organ known as the Corti, which includes inner and outer hair cells, among other cells.
"[A]lthough lead association SNPs are related to sensory hair cell function and their involvement in hearing loss is well established, our cell-specific enrichment analysis revealed hearing loss being also driven, at least in part, by basal cells and spindle cells in the stria vascularis and root cells in the outer sulcus," the authors explained, noting that "lead SNPs mainly related to hair cell and auditory neuron function represent the tip of the iceberg."