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

Abstract

Background Age-related hearing loss is a common, heterogeneous disease with a strong genetic component. More than 100 loci have been reported to be involved in human hearing impairment to date, but most of the genes underlying human adult-onset hearing loss remain unknown. Most genetic studies have focussed on very rare variants (such as family studies and patient cohort screens) or very common variants (genome-wide association studies). However, the contribution of variants present in the human population at intermediate frequencies is hard to quantify using these methods, and as a result, the landscape of variation associated with adult-onset hearing loss remains largely unknown. Results Here we present a study based on exome sequencing and self-reported hearing difficulty in the UK Biobank, a large-scale biomedical database. We have carried out variant load analyses using different minor allele frequency and impact filters, and compared the resulting gene lists to a manually curated list of nearly 700 genes known to be involved in hearing in humans and/or mice. An allele frequency cutoff of 0.1, combined with a high predicted variant impact, was found to be the most effective filter setting for our analysis. We also found that separating the participants by sex produced markedly different gene lists. The gene lists obtained were investigated using gene ontology annotation, functional prioritisation and expression analysis, and this identified good candidates for further study. Conclusions Our results suggest that relatively common as well as rare variants with a high predicted impact contribute to age-related hearing impairment and that the genetic contributions to adult hearing difficulty may differ between the sexes. Our manually curated list of deafness genes is a useful resource for candidate gene prioritisation in hearing loss.

Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology

“… 17 Thus far, over 150 loci have been identified as risk factors for hearing impairment which allowed the calculation of polygenic risk score (PRS) for hearing impairment. 18 However, little is known about the correlation between genetic risk for hearing impairment and pathological and clinical changes before dementia. It is necessary to investigate whether PRS for hearing performance is associated with cognitive decline and pathological changes to further understand the mechanism of how hearing impairment is related to dementia.…”

Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss

“…It includes all the genes listed in the Hereditary Hearing Loss Homepage (hereditaryhearingloss.org/) and genes which, when mutated, result in altered hearing thresholds in mutant mice, as reported by the International Mouse Phenotyping Consortium (www.mousephenotype.org) (average thresholds were individually checked for shifts > 10dB and low variance between individuals). This list is an update of that reported in our previous study (Lewis et al 2022); it consists of 515 genes linked to hearing impairment in mice, 72 genes linked to hearing impairment in humans, and 122 genes linked to hearing impairment in both mice and humans (Figure 1, Suppl. Table 3).…”

“…Variants were filtered for high predicted impact and MAF < 0.1, based on our previous work (Suppl. Table 2, (Lewis et al 2022)), resulting in 29,807 (MUSC) and 21,432 (Twins UK) high quality, high impact variants (Suppl. Figure 3).…”

“…Hearing loss is a common, complex condition with a strong genetic component. More than 700 genes have been found to underlie Mendelian hearing loss in humans and/or mice (reviewed in (Lewis et al 2022)), but large-scale mouse studies suggest there may be as many as 1000 genes which alone can result in hearing impairment when mutated (Ingham et al 2019). Identifying the genes and specific gene variants involved in age-related hearing loss may suggest genes or pathways that can be targeted therapeutically, as well as being useful for diagnosis.…”

“…Some loci have been identified through genome-wide association studies (GWAS) (Ivarsdottir et al 2021;Kalra et al 2020;Wells et al 2019), but very large numbers of people are needed and GWAS chips are limited by their use of common, ancient variants. Whole exome and genome sequencing offer greater scope for identifying causative variants whatever their allele frequency and, indeed, recent studies using exome sequencing (Lewis et al 2022;Praveen et al 2022) suggest that intermediate frequency variants also play a role in hearing difficulty.…”