Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

Abstract

Understanding the genetic underpinnings of disabling hearing loss, which affects ~466 million people worldwide, can provide avenues for new therapeutic target development. We performed a genome-wide association meta-analysis of hearing loss with 125,749 cases and 469,497 controls across five cohorts, including UK Biobank, Geisinger DiscovEHR, the Malmö Diet and Cancer Study, the Mount Sinai BioMe Personalized Medicine Cohort, and FinnGen. We identified 53 loci affecting hearing loss risk, 18 of which are novel, including coding variants in COL9A3 and TMPRSS3. Through exome-sequencing of 108,415 cases and 329,581 controls from the same cohorts, we identified an association with rare predicted loss-of-function variants in a gene that has been uncharacterized in hearing loss, KLHDC7B (odds ratio [OR] = 2.14, P = 5.2 × 10-30), and with coding variants in two genes previously implicated in animal models of hearing loss (SYNJ2, OR = 1.31, P = 1.3 × 10-14; FSCN2, OR = 1.24, P = 4.1 × 10-15). We also observed single-variant and gene-burden associations with 11 genes known to cause Mendelian forms of hearing loss, including an increased risk in heterozygous carriers of mutations in the autosomal recessive hearing loss genes GJB2 (Gly12fs; OR = 1.21, P = 4.2 × 10-11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10-17). Our results show that Mendelian hearing loss genes contribute to the burden of hearing loss in the adult population, and suggest a shared etiology between common and rare forms of hearing loss. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common traits in which risk is modulated by both common and rare variation.

Sex differences, cross-ancestry generalizability, and noise-smoking interactions in the polygenic architecture of hearing loss in adults

“…In the sex-combined GWAS meta-analysis including 501,825 individuals, we identified 54 LDindependent genome-wide significant associations, 14 of which are novel with respect to those identified by previous HL GWAS 8,13,16,54 . In the UKB-NHS-HPFS meta-analysis, three variants showed statistical differences between sexes in their effect size.…”

“…We identified that several genes previously implicated in HL pathogenesis because of their potential involvement in the peripheral structures of the auditory system, which also showed predicted expression differences in various brain regions. For example, while CRIP3 has broad expression in inner and outer hair cells 8 , we observed that transcriptomic changes of this gene in the putamen basal ganglia were associated with HL. Similarly, other genes that may be implicated in HL pathogenesis through both peripheral and central mechanisms include IPP (previously reported as highly expressed in human cochlear, cochlear hair cells, and spiral ganglion cells in mice 54 ), PIK3R3 (previously identified as specific to cell types in the cochlea 70 ), MAST2 (showing differential expression in the development of the inner ear 54 ), and SLC22A6 (identified as related to cochlear impairment 71 ).…”

“…Specifically, rs13399656 in SPTBN1 was the top findings in the sex-difference associations. This gene was previously recognized as a target for β-estradiol as the top upstream regulator 55 and was already associated with altered expression in estrogen-responsive tissues in HL 8 . Similarly, rs1808828 mapped to ABLIM3 and rs11738813 in ARHGEF28 were identified as intronic variants mapped in genes involved in estrogen signaling pathway 56,57 .…”

“…Considering a CADD score threshold of 10 (top 1% of pathogenic variants across the human genome), we further prioritized 24 variants that mapped to 18 unique genes (Supplemental Table 11). Some of them (e.g., ARID5B, CTBP2, and FTO) were previously identified as causal loci of Mendelian forms of deafness and HL 8,16 . Applying the same mapping strategy to the sex-stratified GWS loci, we identified 84 and 46 variants in the credible set for female-and male-specific analyses, respectively (Supplemental Figures 2 and 3).…”

“…Heritability estimates for acquired HL range from 30% up to 70% 7 , highlighting that genetic variation is a key determinant for individual HL risk. More than 100 genes present mutations that result in congenital HL not associated with disorders in other organs or dysmorphic features (nonsyndromic HL) 8,9 . Mutations causing congenital HL affect genes involved in cochlear function, specifically affecting the sensory and mechanosensory cells [10][11][12] .…”