Abstract
Tinnitus, the perception of an auditory phantom sound in the form of ringing, buzzing, roaring, or hissing in the absence of an external sound source, is perceived by ~15% of the population and 2.5% experiences a severely bothersome tinnitus. The contribution of genes on the development of tinnitus is still under debate. The current manuscript reports a pilot Genome Wide Association Study (GWAS) into tinnitus, in a small cohort of 167 independent tinnitus subjects, and 749 non-tinnitus controls, who were collected as part of a cross-sectional study. After genotyping, imputation, and quality checking, the association between the tinnitus phenotype and 4,000,000 single-nucleotide polymorphisms (SNPs) was tested followed by gene set enrichment analysis. None of the SNPs reached the threshold for genome-wide significance (p < 5.0e–8), with the most significant SNPs, situated outside coding genes, reaching a p-value of 3.4e–7. By using the Genetic Analysis of Complex Traits (GACT) software, the percentage of the variance explained by all SNPs in the GWAS was estimated to be 3.2%, indicating that additive genetic effects explain only a small fraction of the tinnitus phenotype. Despite the lack of genome-wide significant SNPs, which is, at least in part, due to the limited sample size of the current study, evidence was found for a genetic involvement in tinnitus. Gene set enrichment analysis showed several metabolic pathways to be significantly enriched with SNPs having a low p-value in the GWAS. These pathways are involved in oxidative stress, endoplasmatic reticulum (ER) stress, and serotonin reception mediated signaling. These results are a promising basis for further research into the genetic basis of tinnitus, including GWAS with larger sample sizes and considering tinnitus subtypes for which a greater genetic contribution is more likely.
Highlights
Tinnitus is the perception of a sound which can be perceived as hissing, ringing, buzzing, or roaring in the absence of an external sound source
None of the single-nucleotide polymorphisms (SNPs) reached the conventional threshold for genome-wide significance (p < 5.0e–8), and the proportion of the variance accounted for by all SNPs together is small, evidence was found for a genetic involvement in tinnitus through gene set enrichment analysis (GSEA)
Throughout the three methods with which the SNPs were tested for association, seven pathways with a significant enrichment in significant SNPs emerged
Summary
Tinnitus is the perception of a sound which can be perceived as hissing, ringing, buzzing, or roaring in the absence of an external sound source. Tinnitus appears as a symptom with increasing prevalence with age. Tinnitus appears to emerge from a complex interaction between aging, diseases, auditory malfunctions, and environmental stressors. In 50% of the cases, tinnitus is attributable to otologic malfunctions (hearing loss, noise trauma, Ménière disease, vestibular schwannoma, temporomandibular junction disorder, ototoxic medications, or substances etc.) (Gilles et al, 2014). Environmental factors increasing the chances to develop tinnitus are recreational and work-related noise exposure (Sindhusake et al, 2003; Kim et al, 2015), smoking, sleep deprivation (Park et al, 2014; Schecklmann et al, 2015), stress (Nondahl et al, 2011), smaller households (Kim et al, 2015), and obesity (Gallus et al, 2015; Martines et al, 2015) whereas high household income and moderate alcohol consumption are considered to be inversely related to tinnitus occurrence (Nondahl et al, 2011; Gallus et al, 2015)
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