Genome-wide analysis implicates inner ear development in Ménière disease

Ménière disease (MD) is a chronic inner ear disorder characterized by recurrent vertigo, fluctuating sensorineural hearing loss, and tinnitus, but its etiology remains poorly understood. We performed a genome-wide meta-analysis of 8,969 MD case subjects and 1,962,542 control subjects across five biobanks, identifying five independent genome-wide significant loci and estimating an observed-scale SNP heritability of 7% (SE 0.8%), indicating a modest but significant contribution of common genetic variation to MD risk. The genome-wide significant signals comprise two independent variants at EYA4, two at EYA1, and one near CYP26A1, with odds ratios between 1.1 and 1.25. Associations at two additional loci, LMO4 and ALDH1A2, fell just below the genome-wide significance threshold (5 × 10^-8

-7). Fine-mapping and integrative functional analyses implicate two convergent biological processes: developmental regulation of the inner ear, involving EYA4, EYA1, and LMO4, and retinoic acid metabolism, with associations near CYP26A1/C1 and ALDH1A2, suggesting disrupted retinoic acid signaling in sensory and fluid-pressure homeostasis. These developmental regulator genes are robustly expressed in fetal and adult human inner ear cell types, supporting a model in which altered developmental programs predispose individuals to adult vestibular and auditory dysfunction. Phenome-wide and genetic correlation analyses further reveal shared genetic architecture between MD and related traits, including vertigo, tinnitus, hearing loss, migraine, and sleep apnea, situating MD within a broader spectrum of sensory and neurological disorders. Collectively, these findings establish a genetic framework for Ménière disease risk and implicate developmental regulators of the inner ear and retinoic acid signaling as key contributing pathways.