Ménière’s disease may begin early in inner ear development

By analyzing genetic data from nearly 2 million people, researchers have unlocked a new scientific understanding of Ménière’s disease, a chronic and often debilitating inner ear disorder. A team from the Perelman School of Medicine at the University of Pennsylvania found evidence that the condition may be linked in part to how the inner ear develops early in life—rather than being caused solely by problems that arise in adulthood, as previously thought. The findings were published in the American Journal of Human Genetics.

Ménière’s disease affects about 1 in 2,000 people and is characterized by episodes of vertigo, fluctuating hearing loss, tinnitus—a ringing, buzzing, clicking, or hissing sound in the ear when no external sound is present—and a feeling of fullness in the ear. While the condition has long been associated with abnormal fluid buildup in the inner ear, its underlying causes have remained poorly understood. This new research provides the first large-scale genetic framework for the disease and points to biological pathways that may help explain both its origins and its symptoms.

“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.”

Biobank data offers new clues

The study combined data from five major biobanks—All of Us, the Million Veteran Program, UK Biobank, FinnGen, and Biobank Japan—bringing together 8,969 cases of Ménière’s disease and nearly two million controls. Using this dataset, researchers identified five regions of the genome linked to disease risk.

The results support a model in which the “blueprint” of the inner ear is established early—potentially even before birth—and small genetic variations can influence its resilience over time. According to the researchers, these early differences may not cause symptoms on their own, but could interact with aging, inflammation, vascular changes, or other environmental factors to trigger the characteristic episodes of Ménière’s disease in adulthood.

New clues point to vitamin A pathway

In addition to developmental genes, the study highlights the importance of a biological pathway involving retinoic acid, a molecule derived from vitamin A that helps regulate organ development and fluid balance. The researchers found signals near genes that control retinoic acid levels, suggesting this pathway may play a role in how the inner ear maintains proper pressure and fluid dynamics. This finding helps connect longstanding theories about fluid imbalance with new insights into developmental biology.

“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 that Ménière’s disease shares genetic connections with related conditions such as hearing loss, tinnitus, vertigo, migraine, and sleep apnea, suggesting that these disorders may have overlapping biological roots.

Early findings highlight a path forward

Despite the advances, the researchers emphasize that genetics explains only a small portion of overall risk—about 7 percent—meaning that the disease cannot be predicted or diagnosed through genetic testing at this time.

“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.”

Future research will focus on laboratory studies using human inner ear models and animal systems to test how these genetic differences influence ear structure, function, and fluid regulation. Larger and more diverse genetic studies will also be needed to refine these findings and explore their potential clinical applications.

As a next step towards leveraging these findings to improve health outcomes, the research team has established a translational research partnership between the MyPennGenome initiative and the Center for Adult-Onset Hearing Loss at Penn Medicine to evaluate preventive genomic sequencing as a scalable, equitable and medically effective strategy for disease interception in hearing loss.

The study was funded by the National Institute of Aging (R01AG085518), the National Institute of Mental Health (R01MH115676), the National Institute of General Medical Sciences (R35GM133708), and the National Institute on Deafness and Other Communication Disorders (R01DC021475).

Editor’s note: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.