Identifying Tinnitus‐Related Genes Based on a Side‐Effect Network Analysis

Elgoyhen, Ana Belén; Langguth, Berthold; Nowak, W; Schecklmann, Martin; Ridder, Dirk De; Vanneste, Sven

doi:10.1038/psp.2013.75

Cited by 24 publications

(10 citation statements)

References 55 publications

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“…One obvious and significant gap is a lack of biomarkers that reflect the consequences of this interactive “tinnitus-causing” network. So far, only one study has attempted to identify protein targets for tinnitus by analyzing the side effect targets for 275 drugs that cause tinnitus (Elgoyhen et al, 2014). Although this is the first study using a network approach to identify targets related to tinnitus, the significance is limited by the fact that tinnitus as a side effect may not necessarily be generated through the drug's pharmacological targets that were analyzed in the study.…”

Section: Introductionmentioning

confidence: 99%

Brain Metabolic Changes in Rats following Acoustic Trauma

Zhu

et al. 2017

Front. Neurosci.

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Acoustic trauma is the most common cause of hearing loss and tinnitus in humans. However, the impact of acoustic trauma on system biology is not fully understood. It has been increasingly recognized that tinnitus caused by acoustic trauma is unlikely to be generated by a single pathological source, but rather a complex network of changes involving not only the auditory system but also systems related to memory, emotion and stress. One obvious and significant gap in tinnitus research is a lack of biomarkers that reflect the consequences of this interactive “tinnitus-causing” network. In this study, we made the first attempt to analyse brain metabolic changes in rats following acoustic trauma using metabolomics, as a pilot study prior to directly linking metabolic changes to tinnitus. Metabolites in 12 different brain regions collected from either sham or acoustic trauma animals were profiled using a gas chromatography mass spectrometry (GC/MS)-based metabolomics platform. After deconvolution of mass spectra and identification of the molecules, the metabolomic data were processed using multivariate statistical analysis. Principal component analysis showed that metabolic patterns varied among different brain regions; however, brain regions with similar functions had a similar metabolite composition. Acoustic trauma did not change the metabolite clusters in these regions. When analyzed within each brain region using the orthogonal projection to latent structures discriminant analysis sub-model, 17 molecules showed distinct separation between control and acoustic trauma groups in the auditory cortex, inferior colliculus, superior colliculus, vestibular nucleus complex (VNC), and cerebellum. Further metabolic pathway impact analysis and the enrichment overview with network analysis suggested the primary involvement of amino acid metabolism, including the alanine, aspartate and glutamate metabolic pathways, the arginine and proline metabolic pathways and the purine metabolic pathway. Our results provide the first metabolomics evidence that acoustic trauma can induce changes in multiple metabolic pathways. This pilot study also suggests that the metabolomic approach has the potential to identify acoustic trauma-specific metabolic shifts in future studies where metabolic changes are correlated with the animal's tinnitus status.

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Section: Introductionmentioning

confidence: 99%

Brain Metabolic Changes in Rats following Acoustic Trauma

Zhu

et al. 2017

Front. Neurosci.

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“…Many genes have been put forward for possibly underlying tinnitus susceptibility but no consensus has been reached so far. An important complicating factor is the heterogeneity in tinnitus causes and types (Sand et al, 2010 ; Pawelczyk et al, 2012 ; Elgoyhen et al, 2014 ; Lopez-Escamez et al, 2016 ). In several monogenic disorders associated with secondary chronic tinnitus, such as neurofibromatosis type II, episodic ataxia type II, osteogenesis imperfecta type I and Fabry disease, causative genes have been identified.…”

Section: Introductionmentioning

confidence: 99%

A Pilot Genome-Wide Association Study Identifies Potential Metabolic Pathways Involved in Tinnitus

et al. 2017

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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.

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“…Elgoyhen et al [30] suggested that ACE is a significant target for tinnitus, and to the best of the authors' knowledge, this was the first time it was determined to be related to tinnitus. According to the authors, the potential role of the brain renin-angiotensin system has been recommended for auditory attention.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-Converting Enzyme (ACE) I/D and Alpha-Adducin (ADD1) G460W Gene Polymorphisms in Turkish Patients with Severe Chronic Tinnitus

Yüce

Sancakdar²,

Bağci³

et al. 2016

Int Adv Otol

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OBJECTIVE:Tinnitus is described as a disturbing sound sensation in the absence of external stimulation. We aimed to investigate whether there is any relationship between severe chronic tinnitus and angiotensin-converting enzyme (ACE) I/D and α-adducin (ADD1) G460W gene polymorphisms. MATERIALS and METHODS:The patient group and control group consisted of 89 and 104 individuals, respectively. The evaluation of tinnitus was performed using the Strukturiertes Tinnitus-Interview (STI). The Tinnitus Handicap Inventory (THI) was used to evaluate the tinnitus severity. Polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques were used for genotyping. RESULTS:With regard to the ACE I/D polymorphism, there was no significant difference in genotype and allele frequencies between the patient group and control group. However, a statistically significant difference was found in genotype (p<0.01) and allele frequencies (p=0.021) of the ADD1 G460W gene polymorphism. Combined genotype analysis showed that the ACE II /ADD1 GW genotype was statistically significantly higher in the patient group than in the control group (X2: 7.15, p=0.007). The odds ratio value of the GW genotype was 2.5 (95% CI=1.4-4.7) (p<0.01). CONCLUSION:Our results demonstrate an association between ADD1 G460W gene polymorphism and susceptibility to severe chronic tinnitus. It was found that the GW genotype increased the disease risk by 2.5-fold compared with other genotypes. This indicates that ADD1 G460W polymorphism could be an important factor in the pathophysiology of tinnitus.

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Identifying Tinnitus‐Related Genes Based on a Side‐Effect Network Analysis

Cited by 24 publications

References 55 publications

Brain Metabolic Changes in Rats following Acoustic Trauma

Brain Metabolic Changes in Rats following Acoustic Trauma

A Pilot Genome-Wide Association Study Identifies Potential Metabolic Pathways Involved in Tinnitus

Angiotensin-Converting Enzyme (ACE) I/D and Alpha-Adducin (ADD1) G460W Gene Polymorphisms in Turkish Patients with Severe Chronic Tinnitus

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