Finnish study identifies disease genes for otosclerosis

The FinnGen research team has identified 27 hereditary risk factors for otosclerosis, a disease that disrupts the function of bones in the middle ear and causes hearing loss. Some of the identified genetic variants are specific to the Finnish population.

The study, led by the University of Helsinki, discovered 23 novel genetic regions and confirmed four previously identified regions associated with the risk of otosclerosis. Many identified genes regulate the development of middle ear bones.

Otosclerosis is the most common treatable cause of hearing loss. The disease is twice as common in women as in men. It is caused by a disturbance of the auditory ossicular chain due to abnormal bone formation and is characterised by hearing loss starting at a relatively young age.

Hereditary factors are known to influence the risk of developing the disease, with up to half of patients having a family member with the disease. The famous composer Ludwig van Beethoven, who became deaf at a young age, is also thought to have suffered from otosclerosis.

The study, now published in Nature Communications by a Finnish-led research team, increases the number of known hereditary risk factors for otosclerosis several-fold.

A mutation in the MEPE gene significantly increases disease risk

The study shows that there are several distinct genetic risk factors for otosclerosis. Most of them are common in the population and increase the risk of otosclerosis only slightly.

Of particular interest was a mutation in the MEPE gene, which occurs in approximately one in three hundred Finns but is very rare in other parts of the world. The mutation alters the structure of the protein encoded by the gene and increases the risk of the disease several-fold.

The link between the MEPE mutation and otosclerosis was further investigated in collaboration with researchers at Stanford University. By examining the expression of the MEPE protein in the bony capsule surrounding the mouse inner ear, the gene was found to be expressed in both developing and mature bone cells.

"Often, biobank-based genomic studies locate large gene regions, but cannot pinpoint individual genes as the cause of disease. By combining experimental setups, we were able to identify the MEPE gene as a likely disease gene", says Joel Rämö, a postdoctoral researcher at the Institute for Molecular Medicine Finland (FIMM) at the University of Helsinki, who carried out the study.

The TGFβ signalling pathway is a promising target for drug development

Extensive health record data linked to the biobank samples allowed the researchers to compare the hereditary risk of otosclerosis and other bone diseases. The results revealed a clear connection. For example, a mutation in the MEPE gene was also found to increase the risk of leg fractures.

In total, twelve of the identified gene regions regulate both the risk of otosclerosis and bone structure elsewhere in the body. Five of the gene regions are likely linked to the transforming growth factor beta (TGFβ) signalling pathway, which is a known regulator of bone formation. Mutations in these genes can also predispose to severe skeletal diseases.

There is currently no drug treatment for otosclerosis. The disease can be treated with sound-amplifying hearing aids and procedures that involve fitting a prosthesis to replace the immobilised part of the auditory chain. Drug development has been delayed by uncertainty about the mechanisms by which the disease develops.

“The TGFβ signalling pathway was markedly associated with the risk of otosclerosis. Drug molecules that act on this signalling pathway have already been developed for the treatment of other diseases. This study will hopefully stimulate interest in studying the same molecules for the treatment of otosclerosis", says Joel Rämö.

The findings were made possible by an extensive international research collaboration comparing genetic data from more than 3500 otosclerosis patients and more than 860 000 controls. The subjects had provided a biobank sample either in Finland, Estonia or the UK.

“The results can be considered significant since there are no drug therapies for otosclerosis and surgery is currently the only effective treatment. However, due to the hereditary nature of the disease, there has been continued interest in identifying target genes for new therapies. The results obtained now motivate follow-up research, which will hopefully lead to new ways of preventing this form of hearing loss that affects a relatively young population", says Professor Antti Mäkitie, Chief Physician at the University of Helsinki and HUS, who participated in the study.

The international study was led by researchers from the Institute for Molecular Medicine Finland (FIMM) at the University of Helsinki and HUS Helsinki University Hospital. The study was carried out in collaboration with research teams from the University of Tartu, the Broad Institute of MIT and Harvard, Massachusetts General Hospital and Stanford University.

Original publication: Genome-wide Screen of Otosclerosis in Population Biobanks: 27 Loci and Shared Associations with Skeletal Structure. Rämö J.T., Kiiskinen T., Seist R., Krebs K., Kanai M., et al. Nature Communications 2023. DOI: 10.1038/s41467-022-32936-3

Contact information

Antti Mäkitie, Professor, Chief Physician

Clinic for Ear, Nose and Throat Diseases

University of Helsinki and HUS


Joel Rämö, Postdoctoral Researcher

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki and the Broad Institute of MIT and Harvard