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

Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease. Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing. These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development. Age-related hearing loss is a common disease which is highly heritable, and more than 150 genes are known to underlie human hearing impairment. However, most of these genes are linked to early-onset, severe forms of deafness, and involve variants which are very rare. Investigating age-related hearing loss is challenging because it is so common; there are many genes which may be involved, with multiple contributing variants which may be rare or common. Here, we have obtained audiometric and genomic data from a cohort of older volunteers (aged 55 and over), which includes a vital control group of 99 older people with good hearing. We have taken two approaches to detecting genes and variants implicated in age-related hearing loss, and followed up this work with a second, smaller, cohort. Our study provides multiple candidate genes for further investigation.