Otosclerosis - identifying genetic contributions to a complex hearing disorder

Otosclerosis is a common form of adult-onset hearing loss. It is a complex disease that most likely involves multiple genetic and environmental factors. We know that a genetic component for otosclerosis exists because of the overwhelming ethnic bias and the fact that nearly half of patients report a family history. Many family linkage studies and candidate gene association studies have been performed; however, disease-causing mutations remain elusive.

The disease is caused by abnormal bone remodeling in the otic capsule, which normally undergoes very little remodeling after development and ossification. This is in stark contrast to the rest of the skeleton, which undergoes bone turn over at a rate of nearly 10% per year. How the otic capsule remains in such a static state is under investigation, but initial studies suggest that bone remodeling inhibitors produced by the inner ear are responsible.

In patients with otosclerosis it is uncertain what events trigger this abnormal bone remodeling. To determine its cause, many environmental and genetic factors have been entertained. However, even with decades of research on the disease, we still know little about its etiology.

My thesis work has aimed to identify molecular and genetic contributors to the disease. To do this, I have performed a global gene expression analysis of otosclerotic tissue to determine what genes are differentially expressed in the disease compared to control tissue. This study has identified a number of differentially expressed genes and pathways potentially involved in the disease. To compliment this work, I also performed a genome-wide association study, in collaboration with a group from Belgium. Together we identified an unexpected gene, RELN, as being associated with otosclerosis in six different European populations. This marks the first successful genome-wide association study for a hearing impairment. I have also identified rare variants in several candidate genes in the TGF-â superfamily in otosclerosis patients. Further analysis of these variants has identified a few that appear to alter protein function, giving us a glimpse of what they may be doing to cause disease.

While we still cannot account for most of the heritability for otosclerosis, we have come a long way in identifying new candidates, in which future analysis will hopefully lead to a better understanding of the disease. In the long term, I hope this work will help provide better treatment options for patients with this disease.