Hereditary hearing impairment

Background

Early studies into hearing loss focused on monogenic forms of hearing loss, where the responsible genes were identified via linkage analysis. However, for the more frequent forms of hearing loss, the genetic architecture is much more complex, and attributable to a complex interplay between many genes, combined with environmental risk factors. These conditions are much harder to study, as they require the analysis of millions of genetic variants in large samples sizes. Our focus lies on two forms of complex hearing loss:

Otosclerosis is a common form of hearing loss with a 0.3-0.4% frequency in the white population. It is characterized by abnormal bone remodeling in the otic capsule and leads to a conductive hearing loss. For familial conditions, a number of genetic regions are known, but no genes were ever identified. We recently identified the involvement of ACAN, encoding the proteoglycan Aggrecan, in sporadic otosclerosis, but it is clear many more genes are involved.

Age related hearing loss (ARHI) is the decline in hearing acuity ageing, mainly in the high frequencies with males more severely affected than females. Recent studies have mainly focused on analyzing ARHI based on questionnaires or medical records data. Studies which include detailed phenotyping, including pure-tone audiometric data (which can be analyzed as a quantitative trait), however, are scarce. One GWAS on a limited number of samples, could not identify individual risk genes, but highlighted the highly polygenic nature of the trait.

Goal

The aim of our projects is to further elucidate the genetic architecture of complex forms of hearing loss. A better knowledge of the pathophysiology of this disorder can lead to better treatments and prevention strategies.

Strategy

For both disorders, a large number of affected individuals and matched controls are available. For the upcoming projects our focus lies on whole exome sequencing, genome-wide association studies and whole genome sequencing. In addition, the role of epigenetic variation will be studied.

Association analysis includes not only the study of common variants, but also the combined effect of rare variation inside or near a gene on the phenotype. It includes linear, logistic an penalized logistic regression, correcting for population stratification by including the principal components of ancestry as covariates.

The results of the association analysis are further processed using gene set enrichment analysis, to pinpoint which metabolic pathways or biological processes are enriched in variants. This is the starting point of further insights into the pathophysiology of these disorders.

Disorders under investigation

Team members

Prof. dr. Guy Van Camp, Prof. dr. Erik Fransen