Whole genome DNA methylation profiles define Meniere's disease subclusters.

Meniere disease (MD) is a cochleo-vestibular syndrome defined by episodes of vertigo associated with tinnitus and sensorineural hearing loss. While MD immune response has been linked to autoinflammation and type 2 cytokines, other molecular mechanisms such as DNA methylation have an emerging yet underexplored role in MD pathophysiology.To understand the role of DNA methylation in MD, we performed whole-genome bisulphite sequencing in MD patients (n = 40) and controls (n = 13) and used differentially methylated cytosines (DMCs) to define clusters, cell types, and biochemical pathways in MD. We found three MD subclusters: Cluster 1 (40% of patients) and Cluster 3 (25%) showed DMC profiles against controls, while Cluster 2 (35%) did not. Significant DMCs from Cluster 1 and Cluster 3 versus Control analysis were annotated to 3033 and 59 unique genes, respectively. Each cluster showed a different gene enrichment; however, the KDMB4 gene had significant upregulated DNA accessibility in a complementary ATAC-seq dataset and showed significant DMCs in both Cluster 1 and Cluster 3. DNA methylation patterns in MD reveal three clusters which are reflective of an underlying difference in pathways related to cytokine stimulus, immunity T-cell, and NK-cell pathways. KDMB4 emerges as a critical MD gene which deserves further research. KEY MESSAGES: We asked if DNA methylation can help understand Meniere's Disease (MD) pathophysiology. DNA methylomes group MD patients into three distinct sub-clusters. DNA methylation in MD reflect difference in pathways related to neurons and cytokine stimulus. The data shows KDMB4 emerging as a key gene that requires further multi-modal investigation.