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 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.

Genetics of Tinnitus: Still in its Infancy

“…The first cross-sectional pilot tinnitus GWAS in ethnically homogeneous individuals between 55 and 65 years old was performed using 167 individuals with tinnitus and 749 non-tinnitus controls from Belgium (Gilles et al, 2017). These patients were previously included in a GWAS for age-related hearing loss in which a polygenic architecture was detected (Fransen et al, 2015).…”

“…Evidence of serotonin receptor mediated pathway involvement has been proposed from an apparent beneficial outcome of antidepressant usage among tinnitus patients (Baldo et al, 2012). Other pathways reaching significance include RAS, vascular smooth muscle contraction, coenzyme A biosynthesis, and NDK dynamin pathways (Gilles et al, 2017). Several limitations described by the authors included limited power to detect significant individual tinnitus-associated SNPs, the sample set was not selectively enriched for tinnitus patients and comprehensive controlling for risk factors was not undertaken.…”

“…The majority of research investigations dissecting the genetics of tinnitus have taken the form of association studies that have revealed few borderline-significant results (Table 2). Recently, a genome-wide association study (GWAS) has identified potential metabolic pathways meriting further investigation (Gilles et al, 2017) and two twin-study cohorts have uncovered heritability estimates that provide pioneering insight into moderate genetic influences for tinnitus (Bogo et al, 2016; Maas et al, 2017). Although an excellent review discussing the genetics of tinnitus that touches upon phenotyping strategies and proposed pathophysiological mechanisms has been recently published (Lopez-Escamez et al, 2016), the present review exclusively emphasizes the genetic studies that have been published to date, discusses emerging data that suggests a complex or multifactorial genetic etiology, and presents an outlook for future research.…”

Role of inheritance in tinnitus: it is time to search the genome

“…Esta heterogeneidad fenotípica que se aprecia en los pacientes con acúfenos explicaría, al menos en parte, porque han fracasado los intentos por encontrar marcadores genéticos en los pacientes con acúfeno crónico (10)(11)(12)(13)(14)(15). Precisamente, la dificultad para definir las características psicoacústicas de los acufenos, intensidad y frecuencia principalmente, permite comprender por qué los estudios de agregación familiar no han demostrado ninguna heredabilidad (16), y que no se haya podido establecer diferencias en la prevalencia de los acúfenos de acuerdo al origen étnico de la población (17)(18)(19).…”

“…Recientemente, Gilles et al (15) han realizado un primer estudio GWAS piloto utilizando una pequeña cohorte de 167 pacientes con acúfenos frente a 749 controles. Después del genotipado de 4x10 6 SNPs ninguno de ellos alcanzó significación, si bien se estimó que el porcentaje de variación explicado por todos los SNPs analizados era de un 3.2%.…”