1. The genomic landscape of Ménière's disease: a path to endolymphatic hydrops
- Author
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Fisch, Kathleen M, Rosenthal, Sara Brin, Mark, Adam, Sasik, Roman, Nasamran, Chanond A, Clifford, Royce, Derebery, M Jennifer, Boussaty, Ely, Jepsen, Kristen, Harris, Jeffrey, and Friedman, Rick A
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Genetics ,Clinical Sciences ,Hearing Loss ,Neurosciences ,Clinical Research ,Human Genome ,Biotechnology ,Brain Disorders ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Neurological ,Ear ,Meniere Disease ,Humans ,Endolymphatic Hydrops ,Animals ,Mice ,Genomics ,Male ,Female ,Retrospective Studies ,Whole Genome Sequencing ,Middle Aged ,Adult ,M & eacute ,ni & egrave ,re's disease ,Whole genome sequencing ,Systems biology ,Network analysis ,Gene discovery ,Ménière's disease ,Information and Computing Sciences ,Medical and Health Sciences ,Bioinformatics ,Biological sciences ,Biomedical and clinical sciences - Abstract
BackgroundMénière's disease (MD) is a disorder of the inner ear that causes episodic bouts of severe dizziness, roaring tinnitus, and fluctuating hearing loss. To date, no targeted therapy exists. As such, we have undertaken a large whole genome sequencing study on carefully phenotyped unilateral MD patients with the goal of gene/pathway discovery and a move towards targeted intervention. This study was a retrospective review of patients with a history of Ménière's disease. Genomic DNA, acquired from saliva samples, was purified and subjected to whole genome sequencing.ResultsStringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell-cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss.ConclusionBy enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.
- Published
- 2024