NEW YORK – In a genome-wide association study, researchers have identified nearly four dozen loci associated with having difficulty hearing or using a hearing aid.
Hearing loss of some form affects about a third of people over the age of 65. While the condition is thought to be partly genetic, only a handful of genes have been linked to age-associated hearing loss.
Using data from the UK Biobank, researchers from King's College London and University College London searched for genetic loci associated with self-reports of either being hard of hearing or of hearing aid use. Through this, they uncovered 44 independent genomic loci associated with hearing loss, many of which have not before been linked to the condition.
"We now know that very many genes are involved in the loss of hearing as we age," co-senior author Frances Williams from the Department of Twin Research & Genetic Epidemiology at King's College said in a statement. "This study has identified a few genes that we already know cause deafness in children, but it has also revealed lots of additional novel genes which point to new biological pathways in hearing." Their results were published yesterday in the American Journal of Human Genetics.
Previous studies of hearing loss have relied on individuals who had undergone assessment by pure tone audiometry, the gold standard for measuring hearing ability, but its requirements of an audiologist, quiet environment, and clinical time are not easily applied to the large numbers needed for GWAS. Instead, Williams and her colleagues used self-reports of hearing difficulty and hearing aid use. That way, they were able to generate a study cohort an order of magnitude larger than previous ones.
They conducted two GWAS, one of hearing difficulty and one of hearing aid use, in about 250,000 individuals — 87,056 people with difficulty hearing and 163,333 controls, and 13,178 people who use hearing aids and 240,740 controls — from the UK Biobank. Through these analyses, the researchers uncovered 41 independent loci associated with difficult hearing and seven independent loci associated with hearing aid use. Four loci were common to both groups, and 34 of them had never been associated with any type of hearing loss before.
After validation in three independent samples, the researchers whittled that list down to two intronic SNPs (rs759016271 in ZNF318 and rs1566129 in NID2) for hearing difficulty and one intronic SNP (rs4597943 in ARHGEF28) for hearing aid use, though 14 others reached nominal significance.
Functional gene annotation of SNPs that met suggestive association with hearing difficulty indicated they were enriched for involvement in a number of processes important for auditory function, such as synaptic signaling, modulation of chemical synaptic transmission, and inner ear morphology.
The researchers examined the expression of three genes — NID2 and ARHGEF28, and CLRN2 — in mouse cochlea.
In mice, they found that NID2 was expressed most predominantly in the epithelial lining inner spiral sulcus between the tectorial membrane and the inner hair cell. Meanwhile, ARHGEF28 was expressed in hair cells and spiral ganglion neuron cell bodies and axons, and CLRN2 was expressed in the inner and outer hair cells. This suggested to the researchers that these genes are involved in metabolic, sensory, and neuronal functions.
According to the researchers, their next step is to tease out how each of the genes they identified in their analysis affects the auditory pathway and whether they might lead to the development of new treatments
"We hope that our findings will help drive forward research into much-needed new therapies for the millions of people worldwide affected by hearing loss as they age," co-senior author Sally Dawson from the UCL Ear Institute said in a statement.