The genomic and epigenomic landscape of otosclerosis

SUMMARY Otosclerosis is an age-related bone disorder characterized by pathological remodeling in the otic capsule of the temporal bone, leading to stapedial fixation and hearing loss. The disease is typically bilateral, progressive, and commonly affects women more than men, with onset usually occurring in the 3rd or 4th decade of life. Although conductive hearing loss can be managed through hearing aids or stapes microsurgery, other clinical features such as sensorineural hearing loss, tinnitus, and vertigo pose greater challenges in treatment. The pathophysiology of otosclerosis it still poorly understood. The otic capsule has a uniquely low bone turnover rate, a process that is disrupted in otosclerosis for unknown reasons. Genetic factors play a critical role in the disease's development, and our preliminary findings, along with others', suggest a genetic overlap with other skeletal disorders. Additionally, while epigenetic mechanisms have been strongly implicated in other aging- related bone diseases, research on their role in otosclerosis is even more limited. Our proposal aims to uncover the molecular basis of otosclerosis by utilizing advanced genomic and epigenomic techniques on a large cohort of unrelated otosclerosis cases and families. This previously gathered cohort, resulting from a long-standing coordinated endeavor by the research team, provides an exceptional opportunity to investigate the molecular aspects of otosclerosis and identify novel genes implicated in the disease. To achieve our aims, we will: 1) Analyze ultrarare and rare genomic variants in a set of large families segregating otosclerosis via genome sequencing. 2) Study common and rare genomic variants in a large cohort of otosclerosis cases and controls via a genome-wide association study using a blended genome-exome sequencing strategy . 3) Identify epigenetic factors implicated in otosclerosis via genome-wide methylation profiling in cases and controls and multi-omics integration of genetic and epigenetic data. All aims are independent and complementary. By the end of this study, we expect to have gained a great insight into the molecular background of otosclerosis. Our results may aid in the development of therapeutic interventions, diagnostic screening, patient management, and family counseling.