Abstract
Age-related hearing impairment (ARHI) affects 46% of the population over the age of 48 and with increasing life expectancy in Western nations, this incidence is likely to rise. The causes for this disorder are still poorly understood but there is known to be a heritable component of around 65%. In addition, epigenetic regulation of gene expression changes over time and may explain many age-related traits. The basis of this research was to explore genetic and epigenetic factors in ARHI to understand better the mechanisms involved in its pathology.Hearing data were obtained from female volunteers of the TwinsUK register using the gold standard measure, air-conduction pure-tone audiometry and a web-based speechin-noise perception test. The prevalence of ARHI in TwinsUK was comparable to previous reports. Heritability estimates based on the classical twin model confirmed a moderate heritability of hearing ability in TwinsUK, supporting the use of this sample in genetic association studies. Genome-wide association with hearing ability was performed in TwinsUK but no genome-wide significant polymorphisms were identified possibly due to inadequate sample size. Accordingly, the data were combined with existing genome-wide association studies (GWAS) of hearing function from the G-EAR
consortium. This meta-analysis resulted in a genome-wide significant association with an exonic SNP of the SIK3 gene encoding salt-inducible kinase 3, a novel gene reported to regulate metabolism and skeletal development via HDAC4. Immunohistochemistry of sik3 in mouse models confirmed striking expression profiles A small epigenome-wide association study of hearing ability in TwinsUK (n=115) revealed an epigenome-wide significant association with a probe in the promoter region of TCF25. Epigenome-wide associations at two highly associated probes (TCF25 and POLE) were replicated in an independent sample from TwinsUK (n=203). DNA methylation at these genes was negatively correlated with expression of the same, indicating gene expression repression by DNA methylation. Furthermore, using identical twins discordant for hearing loss, differentially methylated regions were found at genes ACP6 and CCNDBP1.
This research supports a role of common genetic variants in ARHI, including the novel association with SIK3, which may be essential for healthy hair cell development and maintenance of spiral ganglion cells with increased age. Differentially methylated in hair cells and spiral ganglion cells of mouse cochlea, validating a putative function of SIK3 in hearing ability.
regions were significantly associated with ARHI and showed an effect on gene
expression despite small sample size, supporting a role of epigenetic modifications in ARHI. This research is the first to report genome-wide significant association with SIK3 and epigenome-wide significant associations at TCF25 with ARHI, which may shed light on the pathways involved in this disabling condition.
| Date of Award | 2015 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Frances Williams (Supervisor) & Tim Spector (Supervisor) |