title: A Pilot Genome-Wide Association Study Identifies Potential Metabolic Pathways Involved in Tinnitus.
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 ap-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 lowp-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.
authors.affiliation: Department of Translational Neuroscience, Faculty of Medicine and Health Sciences, University of AntwerpWilrijk, Belgium; University Department of Otorhinolaryngology and Head and Neck Surgery, Antwerp University HospitalEdegem, Belgium; Department of Human and Social Welfare, University College GhentGhent, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: Gilles
authors.affiliation: Center for Medical Genetics, Antwerp University Hospital and University of Antwerp Antwerp, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.affiliation: Department of Translational Neuroscience, Faculty of Medicine and Health Sciences, University of AntwerpWilrijk, Belgium; University Department of Otorhinolaryngology and Head and Neck Surgery, Antwerp University HospitalEdegem, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Van de Heyning
authors.affiliation: Center for Medical Genetics, Antwerp University Hospital and University of AntwerpAntwerp, Belgium; StatUa Center for Statistics, University of AntwerpAntwerp, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
keywords: GWAS; gene set enrichment analysis; genome-wide association study; heritability; oxidative stress; phenotype; serotonin; tinnitus