Polygenic Contribution to Sensorineural Hearing Loss Implicates Novel Risk Loci and Convergence with Congenital Hearing Loss Genes

Abstract Purpose Disabling sensorineural hearing loss (SNHL) affects 5% of the global population. While congenital (CHL) and non-congenital sensorineural hearing loss (SNHL) are both strongly heritable, SNHL is a polygenic disorder, consisting of common genetic variants which individually confer small risks, requiring large studies for significance. Methods We present the first report of a SNHL genome-wide association study (GWAS) from the Million Veteran Program (MVP) (210,240 cases and 265,275 controls), including multi-ancestry analysis, and then combine and contrast this data with a United Kingdom Biobank (UKB) self-reported hearing loss study (87,056 cases and 163,333 controls). We perform functional mapping and annotation, gene prioritization, gene-based and gene-set analysis, and cochlear cell type enrichment, including human single-cell expression data. Results A total of 108 significant loci are identified, including 54 loci containing novel prioritized genes and/or protein-coding genes and implicating 17 known CHL genes. SNP-based partitioned heritability estimates show a 3.26-fold enrichment of CHL relative to other genes. Substantial genetic overlap is seen between MVP and UKB despite differences in phenotypes, demographics, and environmental exposures. Conclusion In this multi-ancestry GWAS, we identify 108 loci with 54 novel genes. Despite the enrichment of CHL genes, 97% of the risk for adult-onset SNHL is captured by SNPs outside of monogenic hearing loss genes. Although SNHL in the UKB and MVP were assessed using different phenotypes, genetic signals between the two cohorts are predominantly shared, and locus discovery is boosted through increased sample size in meta-analysis.