Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment

Fransén, Erik; Bonneux, Sarah; Corneveaux, Jason J.; Schrauwen, Isabelle; Berardino, Federica Di; White, Cory H.; Ohmen, Jeffrey D.; Heyning, Paul Van de; Ambrosetti, Umberto; Huentelman, Matthew J.; Camp, Guy Van; Friedman, Rick A.

doi:10.1038/ejhg.2014.56

Cited by 89 publications

(101 citation statements)

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“…More than 100 loci were identified in familial studies of nonsyndromic hearing loss, with ~30% of the studies failing to identify the specific gene or mutation implicated (http://hereditaryhearingloss.org/). The genetic basis for the more common and complex forms of hearing and balance disorders, such as presbycusis and disequilibrium and falls in the elderly, has been established (Fransen et al, 2014) but remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive catalogue of the coding and non-coding transcripts of the human inner ear

et al. 2016

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The mammalian inner ear consists of the cochlea and the vestibular labyrinth (utricle, saccule, and semicircular canals), which participate in both hearing and balance. Proper development and life-long function of these structures involves a highly complex coordinated system of spatial and temporal gene expression. The characterization of the inner ear transcriptome is likely important for the functional study of auditory and vestibular components, yet, primarily due to tissue unavailability, detailed expression catalogues of the human inner ear remain largely incomplete. We report here, for the first time, comprehensive transcriptome characterization of the adult human cochlea, ampulla, saccule and utricle of the vestibule obtained from patients without hearing abnormalities. Using RNA-Seq, we measured the expression of >50,000 predicted genes corresponding to approximately 200,000 transcripts, in the adult inner ear and compared it to 32 other human tissues. First, we identified genes preferentially expressed in the inner ear, and unique either to the vestibule or cochlea. Next, we examined expression levels of specific groups of potentially interesting RNAs, such as genes implicated in hearing loss, long non-coding RNAs, pseudogenes and transcripts subject to nonsense mediated decay (NMD). We uncover the spatial specificity of expression of these RNAs in the hearing/balance system, and reveal evidence of tissue specific NMD. Lastly, we investigated the non-syndromic deafness loci to which no gene has been mapped, and narrow the list of potential candidates for each locus. These data represent the first high-resolution transcriptome catalogue of the adult human inner ear. A comprehensive identification of coding and non-coding RNAs in the inner ear will enable pathways of auditory and vestibular function to be further defined in the study of hearing and balance. Expression data are freely accessible at https://www.tgen.org/home/research/research-divisions/neurogenomics/supplementary-data/inner-ear-transcriptome.aspx

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Section: Introductionmentioning

confidence: 99%

A comprehensive catalogue of the coding and non-coding transcripts of the human inner ear

et al. 2016

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“…Identification of the genes and processes involved in the maintenance of hearing in adults will similarly lead to an even greater understanding. However, it is likely that multiple pathways interact through positive and negative feedback loops to maintain auditory function [4]. Human genetic diversity, combined with the various experiences of the human condition, may obscure the roles of individual genes and pathways in large scale human studies [4].…”

Section: Discussionmentioning

confidence: 99%

“…For example, hearing loss may develop after exposure to prolonged and excessive noise [2] or to ototoxic drugs such as aminoglycosides [3]. Each individual likely has genetic variation in their susceptibility to these insults [4]. Over a hundred genes that affect hearing loss during development have been identified [5].…”

Section: Introductionmentioning

confidence: 99%

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The Role of the Transcription Factor Foxo3 in Hearing Maintenance: Informed Speculation on a New Player in the Cochlea

White

2016

BioMed Research International

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Molecular genetics has proven to be a powerful approach for understanding early-onset hearing loss. Recent work in late-onset hearing loss uses mouse genetics to identify molecular mechanisms that promote the maintenance of hearing. One such gene, Foxo3, is ontologically involved in preserving mitochondrial function. Significant evidence exists to support the idea that mitochondrial dysfunction is correlated with and can be causal for hearing loss. Foxo3 is also ontologically implicated in driving the circadian cycle, which has recently been shown to influence the molecular response to noise damage. In this review, the molecular framework connecting these cellular processes is discussed in relation to the cellular pathologies observed in human specimens of late-onset hearing loss. In bringing these observations together, the possibility arises that distinct molecular mechanisms work in multiple cell types to preserve hearing. This diversity offers great opportunities to understand and manipulate genetic processes for therapeutic gain.

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“…The fourth GWA study was undertaken into the hearing status of 3,614 individuals (all aged 44-45 years) in the British 1958 Birth Cohort and again failed to find a significant association but provided the basis for the subsequent characterisation of a novel hearing gene, ESRRG, in a knock-out mouse model [13]. The fifth by Fransen et al [14] is an extension of the first GWA study, employing a larger sample set. This recent study revealed no significant GWAs for ARHL and also did not add support to any of the previously reported associations in GRM7 or GRM8 .…”

Section: The Need For An Animal Modelmentioning

confidence: 99%

The Mouse as a Model for Age-Related Hearing Loss - A Mini-Review

Bowl

Dawson²

2014

Gerontology

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The most common form of sensory disability is age-related hearing loss (ARHL), also referred to as presbycusis. ARHL is a complex disorder with a mixture of genetic and environmental components, a combination that leads to a progressive decline in hearing function with increased age. In the last 15 years, there has been a vast increase in our knowledge of the genes that underlie congenital deafness and the critical components of hearing. In contrast, knowledge of the pathological processes involved in ARHL remains very limited. The mouse has proved an essential tool in the identification of early-onset deafness genes and in revealing the basic mechanisms of hearing. As focus is now turning toward elucidating the most common form of hearing loss, ARHL, the mouse will again play a fundamental role in this research. Here, we review the need for an animal model and discuss the suitability of the mouse as an ARHL model. Finally, we outline the ways in which hearing researchers are utilising the mouse in the investigation of ARHL and provide perspectives on the need for these data to be integrated with the results of human genetic studies.

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Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment

Cited by 89 publications

References 18 publications

A comprehensive catalogue of the coding and non-coding transcripts of the human inner ear

A comprehensive catalogue of the coding and non-coding transcripts of the human inner ear

The Role of the Transcription Factor Foxo3 in Hearing Maintenance: Informed Speculation on a New Player in the Cochlea

The Mouse as a Model for Age-Related Hearing Loss - A Mini-Review

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