Genetic Inheritance and Its Contribution to Tinnitus

Amanat, Sana; Gallego‐Martinez, Alvaro; López-Escámez, José A.

doi:10.1007/7854_2020_155

Cited by 8 publications

(10 citation statements)

References 56 publications

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“…Evidence for a genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype [ 8 , 9 ].The extreme phenotype (EP) strategy has been used in exome sequencing studies to investigate the genetic contribution of rare variants in rare and complex disorders [ 10 , 11 ]. Individuals with EP are characterized by extreme clinically relevant attributes, toxic effects, or extreme responses to a treatment.…”

Section: Introductionmentioning

confidence: 99%

Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

et al. 2021

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Background tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 ( p < 2E −04 ), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes ( p < 2E −02 ). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus . ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons.

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Section: Introductionmentioning

confidence: 99%

Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

et al. 2021

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“…However, well-defined deep phenotyping of patients with tinnitus will continue to be a challenge but an important hurdle for selecting homogeneous patient groups and reducing the possibilities of false-negative results, which will be essential, as large sequencing cohorts are increasingly available. Well-defined clinical phenotypes must consider aspects such as early age of onset, sex, co-morbidities such as hearing loss and stress/anxiety, audiometry, tinnitus questionnaires, and psychoacoustic evaluations [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Here, under a complex disease model hypothesis and by only selecting a small number of patients with severe tinnitus (extreme phenotype), the large phenotypic heterogeneity can be greatly narrowed. A single variant and gene burden analyses can be performed to identify an enrichment of rare variants with large effect sizes that associate with an extreme phenotype [ 33 ].…”

Section: Extreme Phenotype Approachmentioning

confidence: 99%

The Road Traveled and Journey Ahead for the Genetics and Genomics of Tinnitus

Vona

2022

Mol Diagn Ther

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The feasibility to unravel genetic and genomic signatures for disorders affecting the auditory system has accelerated since arriving in the post-genomics era roughly 20 years ago. Newly emerging studies have provided initial landmarks signaling heritability and thus, a genetic link, to severe tinnitus. Tinnitus, the phantom perception of ringing in the ears, is experienced by at least 15% of the adult population and can be extremely disabling. Despite its ubiquity, there is no cure for tinnitus and modalities offering relief are often of limited success. Because tinnitus is frequently reported in patients with acquired conductive or sensorineural hearing impairment, it has been widely accepted that tinnitus is secondary to and a symptom arising from hearing impairment. However, tinnitus has also been identified in the absence of auditory dysfunction and in young individuals, resulting in a debate about its origins. Genetics studies have identified severe tinnitus as a complex disorder arising from gene and environment interactions, refining its classification as a neurological disorder and, in at least a subset of patients, it appears not as a symptom of another health issue. This current opinion summarizes several recent studies that have challenged a long-accepted dogma and postulates how this information could eventually be used in the future to help patients. It is with great hope that this knowledge opens translational paths to provide relief for the many who suffer from the burden of tinnitus on a daily basis.

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“…In this sense, the lack of tinnitus habituation could be explained as a result of a reduced resilience strategy. Here, for example, the absence of hereditary contributors to enhanced distress, which have been shown to increase susceptibility to tinnitus (Amanat et al 2020 ; Lopez-Escamez and Amanat 2020 ; Ruan et al 2018 ; Szczepek et al 2019 ), including the BDNF Val 66 Met polymorphism (Vanneste et al 2021 ), have to be regarded in the context of a possible contribution to tinnitus resilience and long-term habituation.…”

Section: Introductionmentioning

confidence: 99%

Too Blind to See the Elephant? Why Neuroscientists Ought to Be Interested in Tinnitus

Knipper

Mazurek

Dijk

et al. 2021

JARO

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A curative therapy for tinnitus currently does not exist. One may actually exist but cannot currently be causally linked to tinnitus due to the lack of consistency of concepts about the neural correlate of tinnitus. Depending on predictions, these concepts would require either a suppression or enhancement of brain activity or an increase in inhibition or disinhibition. Although procedures with a potential to silence tinnitus may exist, the lack of rationale for their curative success hampers an optimization of therapeutic protocols. We discuss here six candidate contributors to tinnitus that have been suggested by a variety of scientific experts in the field and that were addressed in a virtual panel discussion at the ARO round table in February 2021. In this discussion, several potential tinnitus contributors were considered: (i) inhibitory circuits, (ii) attention, (iii) stress, (iv) unidentified sub-entities, (v) maladaptive information transmission, and (vi) minor cochlear deafferentation. Finally, (vii) some potential therapeutic approaches were discussed. The results of this discussion is reflected here in view of potential blind spots that may still remain and that have been ignored in most tinnitus literature. We strongly suggest to consider the high impact of connecting the controversial findings to unravel the whole complexity of the tinnitus phenomenon; an essential prerequisite for establishing suitable therapeutic approaches.

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Genetic Inheritance and Its Contribution to Tinnitus

Cited by 8 publications

References 56 publications

Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

The Road Traveled and Journey Ahead for the Genetics and Genomics of Tinnitus

Too Blind to See the Elephant? Why Neuroscientists Ought to Be Interested in Tinnitus

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