Genome-wide analysis implicates inner ear development in Ménière disease

Area of Science:

• Genetics
• Otolaryngology
• Neuroscience

Background:

• Ménière disease (MD) is a chronic inner ear condition with unknown causes, presenting with vertigo, hearing loss, and tinnitus.
• Understanding the genetic basis of MD is crucial for identifying risk factors and potential therapeutic targets.

Purpose of the Study:

• To identify genetic loci associated with Ménière disease risk through a large-scale genome-wide meta-analysis.
• To explore the biological pathways involved in MD pathogenesis, including inner ear development and retinoic acid signaling.

Main Methods:

• Genome-wide meta-analysis of 8,969 MD cases and 1,962,542 controls across five biobanks.
• Fine-mapping and integrative functional analyses to identify candidate genes and pathways.
• Phenome-wide and genetic correlation analyses to explore shared genetic architecture with related traits.

Main Results:

• Identified five independent genome-wide significant loci for MD, with common genetic variation contributing 7% to MD risk.
• Key genes implicated include EYA4, EYA1, CYP26A1, LMO4, and ALDH1A2, involved in inner ear development and retinoic acid metabolism.
• MD shares genetic architecture with vertigo, tinnitus, hearing loss, migraine, and sleep apnea.

Conclusions:

• Common genetic variations play a significant role in Ménière disease susceptibility.
• Disrupted inner ear development and retinoic acid signaling are implicated in MD pathogenesis.
• MD is situated within a broader spectrum of sensory and neurological disorders with shared genetic underpinnings.