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

Abstract

To better understand the genetics of hearing loss, we performed a genome-wide association meta-analysis with 125,749 cases and 469,497 controls across five cohorts. We identified 53/c loci affecting hearing loss risk, including common coding variants in COL9A3 and TMPRSS3. Through exome sequencing of 108,415 cases and 329,581 controls, we observed rare coding associations with 11 Mendelian hearing loss genes, including additive effects in known hearing loss genes GJB2 (Gly12fs; odds ratio [OR] = 1.21, P = 4.2 × 10−11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10−17). We also identified hearing loss associations with rare coding variants in FSCN2 (OR = 1.14, P = 1.9 × 10−15) and KLHDC7B (OR = 2.14, P = 5.2 × 10−30). Our results suggest a shared etiology between Mendelian and common hearing loss in adults. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common disorders where both common and rare variation contribute to risk.

Investigating the characteristics of genes and variants associated with self-reported hearing difficulty in older adults in the UK Biobank

“…Increasing the MAF cutoff resulted in a significant enrichment in highly variable genes, and reducing it reduced the number of genes in the list, although the enrichment in deafness genes remained significant at all the cutoffs we tested (Table 1 ). This suggests that relatively common variants (MAF < 0.1) with a high predicted impact do contribute to hearing impairment, which correlates with the findings of another recent UK Biobank study [ 10 ], which reports that 16.8% of SNP heritability is contributed by “low-frequency variants” (0.001 < MAF ≤ 0.05). This is lower than our chosen cutoff (MAF < 0.1), but still higher than the standard cutoff of 0.001 recommended for autosomal dominant hearing loss [ 41 ].…”

“…On the other end of the scale, looking at common variants, very large genome-wide association studies (GWAS) have recently uncovered several new loci [ 8 , 9 ], but because GWAS work by identifying markers linked to disease loci, they cannot detect recent mutations or those which are not widespread throughout the population. A recent GWAS on hearing loss (made available as a preprint), which reports both common and rare variant association analyses, found that the rare variant association signals were mostly independent of the common variant associations nearby, confirming that it is important to include consideration of rare variants in the genetic landscape of ARHL [ 10 ].…”

Investigating the Characteristics of Genes and Variants Associated with Self-Reported Hearing Difficulty in Older Adults in the UK Biobank

“…Increasing the MAF cutoff resulted in a significant enrichment in highly variable genes, and reducing it reduced the number of genes in the list, although the enrichment in deafness genes remained significant at all the cutoffs we tested (Table 1). This suggests that relatively common variants (MAF < 0.1) with a high predicted impact do contribute to hearing impairment, which correlates with the findings of another recent UK Biobank study [10], which reports that 16.8% of SNP heritability is contributed by “low-frequency variants” (0.001 < MAF ≤ 0.05). This is lower than our chosen cutoff (MAF < 0.1), but still higher than the standard cutoff of 0.001 recommended for autosomal dominant hearing loss [46].…”

“…Those genes identified by multiple studies are obvious candidates for involvement in ARHL, but the differences in loci identified using the GWAS approach suggest there are many more to investigate, and the results of our exome sequencing analysis support that as well as suggesting further candidates (Table 2). It has recently been observed that rare variants do not account for the GWAS hits of common markers [10], so it is unsurprising to find different variants and different genes associated with ARHL in GWAS compared with exome/genome sequence analysis studies.…”

“…Although many of these known deafness genes have only been linked to early-onset, severe hearing impairment, they are still good candidates for involvement in milder hearing impairment, since different variants can result in very different phenotypes. For example, different variants in TMC1 have been shown to result in either prelingual profound hearing loss or postlingual progressive hearing loss [76, 77], and several recent large-scale studies looking at adult-onset hearing loss have found multiple missense variants in Mendelian deafness genes with milder effects than previously reported [5, 10, 48].…”