TY - JOUR
T1 - Functional analysis of candidate genes from Genome-Wide Association Studies of hearing.
AU - Ingham, Neil Jon
AU - Rook, Victoria
AU - Di Domenico, Francesca
AU - James, Elysia
AU - Lewis, Morag Ann
AU - Girotto, Giorgia
AU - Buniello, Annalisa
AU - Steel, Karen Penelope
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
KW - A430005L14Rik
KW - Age-related hearing loss
KW - Auditory brainstem response
KW - Dclk1
KW - Evoked potentials
KW - Gene expression
KW - Genome-wide association studies
KW - Mammalian auditory system
KW - Mouse mutants
UR - http://www.scopus.com/inward/record.url?scp=85077661359&partnerID=8YFLogxK
U2 - 10.1016/j.heares.2019.107879
DO - 10.1016/j.heares.2019.107879
M3 - Article
SN - 0378-5955
VL - 387
JO - Hearing Research
JF - Hearing Research
M1 - 107879
ER -