Genome-wide association study meta-analysis brings monogenic hearing loss genes into the polygenic realm
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
For 5% of the global population, disabling age-related and noise-induced hearing loss (SNHL) is associated with isolation, depression, cognitive decline, and dementia. On an economic level, SNHL is correlated with decreased employment, particularly for manual labor. Here we present one of the largest genome-wide association studies (GWAS) on SNHL to date, using clinical diagnosis from the Million Veteran Program (MVP) (210,240 cases and 265,275 controls). GWAS findings are contrasted and then meta-analyzed with the United Kingdom Biobank (UKB) self-reported hearing loss GWAS (87,056 cases and 163,333 controls). We identify substantial genetic overlap despite differences in demographics, experiences, and source of phenotypes. Meta-analysis of the two cohorts identifies 108 loci, including novel and known familial hearing loss genes. Significant gene ontology pathways included "sensory perception of mechanical stimulus," "ear development," "actin-binding," and "cytoskeletal protein binding," indicative of mechanosensory structure and function in the cochlea. Eighteen congenital hearing loss genes are suggested, expressing proteins in subcellular regions of inner and outer hair cells, including stereocilia, rootlets, and mechanoelectrical transduction tip-links, as well as supporting cells, Type 1 neurons and stria vascularis. SNP-based heritability estimates over familial hearing loss genes showed a 3.26 fold enrichment relative to genes not listed as familial hearing loss genes. However, due to the small number of familial hearing loss genes, the majority of heritability was accounted for by genes not yet designated as hearing loss genes.
