Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank

Abstract

Tinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E−08), rs4900545 (p = 1.8E−08) and 14:103042287_CT_C (p = 3.50E−08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E−06.

Genome-wide association study identifies new loci associated with noise-induced tinnitus in Chinese populations

“…Up to now, two GWASs of tinnitus in European populations have been reported [ 10 , 37 ]. The first GWAS of tinnitus consists of 167 tinnitus subjects and 749 non-tinnitus subjects [ 10 ], and none of the SNPs reach the threshold for genome-wide significance ( P < 5.0 × 10 − 8 ).…”

“…However, several metabolic pathways showed significant associations. The other GWAS of tinnitus consists of 14,829 tinnitus subjects 119,600 subjects who have never experienced tinnitus [ 37 ]. One SNP (rs4906228) upstream of the RCOR1 gene showed genome-wide significant association with tinnitus ( P = 1.7 × 10 8 ).…”

Genetic predisposition to tinnitus in the UK Biobank population

“…This was reflected in our results, as even with the minor reduction in power combined with the normally disperse effects of tinnitus’s low heritability, we were still able to determine a number of suggestive SNPs, along with our top hit, WDPCP . Additionally, this approach to phenotypic cohort sorting, along with tinnitus’s complex heritability pattern, may also serve to explain why our cohort found no overlaps with those of other tinnitus GWAS 23 , 25 , 26 . Even GWAS investigating larger populations of more general tinnitus lack overlap with one another, indicating that further characterization of identified SNPs and their influence on varying tinnitus phenotypes is needed.…”

“…Though our GWAS is not the first to be conducted on the participants in the UK Biobank cohort, we made use of a novel set of data, the whole exome sequences, which could lead to completely distinct loci from those previously found 25 , 26 . Because the majority of our data spanned protein-coding and adjacent regions of the genome, six of our SNPs resulted in direct alterations to the amino acid sequence.…”

“…Contrary to our study, this GWAS used genotyping array data and did not control for any noise exposure, in part because the Million Veterans Program database does not include equivalent measures. The fourth and most recent study, also in the UK Biobank population, focused on participants that reported frequent tinnitus and found three significant near the RCOR1 gene, along with 11 other suggestive loci 26 . However, because tinnitus often manifests as a consequence of intense noise levels, a GWAS must consider the differences in environmental exposures to correctly parse out which individuals genuinely have a predisposition to tinnitus, rather than those that are simply missing the correct environmental circumstances.…”