Researchers at the University of Pennsylvania have identified genetic evidence suggesting that Ménière’s disease may be linked, in part, to early developmental pathways in the inner ear, offering a new framework for understanding a disorder that has long been difficult to explain biologically.
The findings, published in The American Journal of Human Genetics, come from what the researchers describe as a large-scale genome-wide analysis of Ménière’s disease. The study analyzed genetic data from 8,969 individuals with Ménière’s disease and 1,962,542 control subjects across five major biobanks: All of Us, the Million Veteran Program, UK Biobank, FinnGen, and Biobank Japan.
Ménière’s disease is a chronic inner ear disorder characterized by recurrent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and a feeling of fullness or pressure in the ear. Although the condition has often been associated with endolymphatic hydrops—an abnormal buildup of fluid in the inner ear—its underlying causes have remained poorly understood.
“Our findings suggest that Ménière’s disease is not just something that arises from fluid imbalance later in life,” said Douglas Epstein, PhD, a professor and vice chair of Genetics at Penn, and senior co-author of the study. “Instead, it may begin with subtle differences in how the inner ear is built in the first place. These differences are usually small and within the normal range, but they may make some people more vulnerable to problems decades later.”
Largest Genetic Study of Ménière’s Disease to Date
The study identified five independent genome-wide significant loci associated with Ménière’s disease risk. These signals were found near genes involved in inner ear development and retinoic acid signaling, a pathway related to vitamin A metabolism that plays an important role in embryonic development and tissue patterning.
The strongest findings involved genes known as EYA4 and EYA1, both of which are involved in inner ear development. The researchers also identified a significant signal near CYP26A1, a gene involved in regulating retinoic acid levels, and highlighted suggestive signals near LMO4 and ALDH1A2, which also have biological relevance to inner ear development and retinoic acid metabolism.
Together, the findings support a model in which subtle differences in the developmental “blueprint” of the inner ear may increase susceptibility to Ménière’s disease later in life. These differences may not cause symptoms on their own, but could interact with aging, inflammation, vascular changes, fluid regulation, or other biological and environmental factors over time.
Developmental Genes and Vitamin A Pathway Emerge
The results point to two broad biological themes: developmental regulation of the inner ear and retinoic acid signaling. Retinoic acid is derived from vitamin A and helps regulate organ development, including structures involved in sensory function and fluid-pressure homeostasis.
The researchers found evidence that genes controlling retinoic acid levels may be involved in Ménière’s disease risk. This finding may help connect older theories about fluid imbalance in the inner ear with newer insights into developmental biology and genetic regulation.
“This gives us a much clearer starting point,” said Bogdan Pasaniuc, PhD, a professor of Genetics and senior co-author of the study. “For a long time, Ménière’s disease has been difficult to study because we didn’t know what biological systems to focus on. Now we have strong evidence pointing to specific pathways that matter.”
The study also found genetic overlap between Ménière’s disease and related conditions, including vertigo, tinnitus, sensorineural hearing loss, migraine, and sleep apnea. According to the researchers, this suggests that Ménière’s disease may share biological roots with a broader group of sensory and neurological disorders.
Genetics Explains Only Part of the Risk
Although the study provides an important genetic framework, the researchers emphasize that genetics accounts for only a modest portion of overall risk. The analysis estimated that common genetic variants explain about 7 percent of Ménière’s disease risk, meaning that the condition cannot currently be predicted or diagnosed through genetic testing.
The findings also suggest that common genetic variants associated with sporadic Ménière’s disease are different from rare variants previously linked to familial forms of the disorder. The researchers note that these may represent complementary layers of risk rather than competing explanations.
“This is an important step forward, but it’s still early,” said Iain Mathieson, PhD, an associate professor of genetics and senior co-author of the study. “What we’ve done is map out where to look. The next challenge is to understand exactly how the genes we’ve identified affect the inner ear and whether that knowledge can eventually lead to better treatments.”
Next Steps for Research and Treatment
Future research will focus on laboratory studies using human inner ear models and animal systems to investigate how the identified genetic differences affect ear structure, function, and fluid regulation. Larger and more diverse genetic studies will also be needed to refine the findings and better understand how genetic risk interacts with other factors.
The Penn Medicine team has also established a translational research partnership between the MyPennGenome initiative and the Center for Adult-Onset Hearing Loss at Penn Medicine. The partnership will evaluate preventive genomic sequencing as a scalable, equitable, and medically effective strategy for disease interception in hearing loss.
While the findings are not yet ready to guide clinical testing or treatment decisions, they provide a new biological roadmap for studying Ménière’s disease and may help researchers identify more targeted approaches to diagnosis, prevention, and therapy in the future.
The study was funded by the National Institute on Aging, the National Institute of Mental Health, the National Institute of General Medical Sciences, and the National Institute on Deafness and Other Communication Disorders.
Reference:
- Shi Z, Mandla R, Li J, et al. Genome-wide analysis implicates inner ear development in Ménière disease. The American Journal of Human Genetics. Published online July 2, 2026. doi:10.1016/j.ajhg.2026.05.011.
