Adult-onset hearing difficulty is the most common sensory impairment characterized by a non-syndromic bilateral, sensorineural hearing loss in the aging population. Nearly a third of individuals are affected by disabling hearing loss by the age of 65. It can lead to adverse mental health conditions, such as social isolation and depression, and it has recently been identified as a risk factor for dementia. Despite the seriousness of this impairment, hearing amplification devices are the only treatment option currently available for adult-onset hearing difficulties.
From a genetic perspective, adult onset hearing difficulty is expected to be a highly heterogeneous trait given that more than 150 genetic loci have been identified in non-syndromic congenital hearing loss alone. To date, however, five genomic loci have been significantly associated with adult hearing difficulties in previous genome-wide association studies (GWASs), only two of which were replicated in independent population samples. Understanding the genetic etiology of adult-onset hearing impairment may shed some light on the pathophysiology of the condition and ultimately facilitates the development of novel therapeutic or preventative interventions.
In this context, researchers performed a GWAS for two hearing phenotypes: hearing difficulty (HDiff) and hearing aid use (HAid). Participants included volunteers in the UK Biobank (UKBB) aged between 40 and 69 years. UKBB participants were categorized using a case-control design based on responses to questions regarding HDiff and HAid. HDiff case subjects responded ‘‘Yes’’ to both of the questions ‘‘Do you have any difficulty with your hearing?’’ and ‘‘Do you find it difficult to follow a conversation if there is background noise (such as TV, radio, children playing)?’’ HDiff control subjects were selected if their response to both of these questions was ‘‘No.’’ Participants with any other combination of responses were removed. Up to 500,000 samples in UKBB were genotyped and a total of 250,389 samples (87,056 case subjects and 163,333 control subjects) were used for association analysis of HDiff. Forty-four independent genome-wide significant SNP associations were identified. Two independent associations, including rs6453022, were found near the ARHGEF28 locus, which is a novel finding. It represents a more than 400-fold increase in the number of reported genome-wide significant SNP associations and a 9-fold increase in independent genomic loci for age-related phenotypes and provides a major breakthrough in revealing the genetic architecture of ARHI. The gene encodes for Rho Guanine Nucleotide Exchange Factor 28 which has been suggested to be involved in neuronal function or maintenance. While ten loci, including rs9493627 located near EYA Transcriptional Coactivator And Phosphatase 4 (EYA4), have previously been linked to some form of hearing loss either in mouse models or humans. Other SNPs near ARHGEF28 and EYA4 were also associated with HAid.
One of the limitations of the study is that the age of onset of HDiff or HAid prescription was not confirmed, making an accurate diagnosis of adult hearing difficulty challenging. In this study, in order to lower the possibility to include individuals with congenital hearing impairment in the case subject, a minor allele frequency cut-off of 0.01 (i.e., higher than the known frequency of variants involved in congenital deafness) and by excluding participants who selected ‘‘I am completely deaf’’ in the UKBB questionnaire. To sum, the new findings in the study using large cohorts such as UKBB provide therapeutic opportunities in age-related hearing difficulty and possibly dementia. Read more about the study here: https://www.ncbi.nlm.nih.gov/pubmed/31564434
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