Functional analysis of candidate genes from genome-wide association studies of hearing

Autor: Karen P. Steel, Annalisa Buniello, Francesca Di Domenico, Neil J. Ingham, Victoria Rook, Morag A. Lewis, Giorgia Girotto, Elysia James
Přispěvatelé: Ingham, N. J., Rook, V., Di Domenico, F., James, E., Lewis, M. A., Girotto, G., Buniello, A., Steel, K. P.
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Genome-wide association studie
Candidate gene
Evoked potential
df
degrees of freedom
Genome-wide association study
Disease
medicine.disease_cause
GWAS
genome-wide association studies
Genome-wide association studies
Doublecortin-Like Kinases
0302 clinical medicine
Hearing
Risk Factors
ANOVA
analysis of variance
Genetics
Mutation
Age Factors
Intracellular Signaling Peptides and Proteins
A430005L14Rik
Age-related hearing loss
Auditory brainstem response
Dclk1
Evoked potentials
Gene expression
Mammalian auditory system
Mouse mutants
Presbycusis
Sensory Systems
Phenotype
Age-related hearing lo
Auditory Perception
Female
medicine.symptom
Hearing loss
Mice
Transgenic
Protein Serine-Threonine Kinases
Biology
Risk Assessment
Article
03 medical and health sciences
Evoked Potentials
Auditory
Brain Stem
medicine
Animals
Humans
Genetic Predisposition to Disease
Gene
Genetic association
qRT-PCR
quantitative real time polymerase chain reaction
EP
endocochlear potential
Genetic Variation
ABR
auditory brainstem response
Mice
Mutant Strains
Genetic architecture
Mice
Inbred C57BL
ARHL
age-related hearing loss
030104 developmental biology
Hearing Loss
Noise-Induced
030217 neurology & neurosurgery
Genome-Wide Association Study
Zdroj: Hearing Research
ISSN: 0378-5955
DOI: 10.1016/j.heares.2019.107879
Popis: The underlying causes of age-related hearing loss (ARHL) are not well understood, but it is clear from heritability estimates that genetics plays a role in addition to environmental factors. Genome-wide association studies (GWAS) in human populations can point to candidate genes that may be involved in ARHL, but follow-up analysis is needed to assess the role of these genes in the disease process. Some genetic variants may contribute a small amount to a disease, while other variants may have a large effect size, but the genetic architecture of ARHL is not yet well-defined. In this study, we asked if a set of 17 candidate genes highlighted by early GWAS reports of ARHL have detectable effects on hearing by knocking down expression levels of each gene in the mouse and analysing auditory function. We found two of the genes have an impact on hearing. Mutation of Dclk1 led to late-onset progressive increase in ABR thresholds and the A430005L14Rik (C1orf174) mutants showed worse recovery from noise-induced damage than controls. We did not detect any abnormal responses in the remaining 15 mutant lines either in thresholds or from our battery of suprathreshold ABR tests, and we discuss the possible reasons for this.
Highlights • Dclk1 may play a role in progressive age-related hearing loss. • A430005L14Rik may play a role in the susceptibility of the auditory system to noise-damage. • Fifteen other candidate genes (from GWAS) knocked out or knocked down in mutant mice do not lead to changes in ABRs.
Databáze: OpenAIRE
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