Migraine (MI) is the most common neurological disease, affecting with 20% of the world population. A subset of 25% of MI patients showcase concurrent vestibular symptoms, which may classify as vestibular migraine (VM). Meniere's disease (MD) is a complex inner ear disorder defined by episodes of vertigo associated with tinnitus and sensorineural hearing loss with a significant autoimmune/autoinflammatory contribution, which symptoms overlap with VM. Blood samples from 18 patients with MI (5), VM (5) and MD (8) and 6 controls were collected and compared in a case–control study. Droplet‐isolated nuclei from mononuclear cells used to generate scRNAseq and scATACseq data sets from MI, VM and MD. MI and VM have no differences in their immune transcriptome; therefore, they were considered as a single cluster for further analyses. Natural Killer (NK) cells transcriptomic data support a polarisation triggered by Type 1 innate immune cells via the release of interleukin (IL)‐12, IL‐15 and IL‐18. According to the monocyte scRNAseq data, there were two MD clusters, one inactive and one driven by monocytes. The unique pathways of the MI + VM cluster were cellular responses to metal ions, whereas MD monocyte‐driven cluster pathways showed responses to biotic stimuli. MI and MD have different immune responses. These findings support that MI and VM have a Type 1 immune lymphoid cell response, and that there are two clusters of MD patients, one inactive and one Monocyte‐driven.

Purpose: The stria vascularis (SV) is a secretory epithelium that maintains fluid homeostasis and generates the endocochlear potential in the cochlear duct. Multiomic studies have identified genes in the SV that could contribute to the pathogenesis of Menière’s Disease (MD), a disorder defined by episodic vertigo, sensorineural hearing loss, and tinnitus. This systematic review identified genes expressed in the SV cell types (marginal, intermediate, and basal) and gap junction proteins to evaluate their pathophysiological connections to MD. Methods: We conducted a literature search on 1293 articles relevant to MD and SV that were screened for SV genes involved in MD. Following quality assessment, 130 studies met the inclusion criteria, comprising 26 human studies, 101 animal studies, and three human-animal studies. Results: Seven immune-related and six auditory-related genes were identified: CACNA1D, ESRRB, HGF, KCNE1, MDH1, QSOX1, and SLC12A2 (marginal cells); ACTB, TMEM176A, and TMEM176B (intermediate cells); and ACTN1, COL11A2, and GSTM1 (basal cells). Gene-set-enrichment-analysis revealed pathways involving gap-junction assembly and electrical coupling. International Mouse Phenotyping Consortium data showed Gja1 and Kcne1 knockouts have immune system abnormalities. Single-cell RNA sequencing data of the lateral wall revealed high expression of Coch, Dtna, and Prkcb in fibrocytes, Reisner’s cells, and immune cells. Furthermore, TWEAK released from intermediate cells and bound to its receptor (TNFRSF12A) in the marginal cells may upregulate NF-κB inflammatory response in MD patients. Conclusion: We hypothesize that some SV genes may contribute to the audiovestibular phenotype in MD, but most of them play a role in the altered immune response found in Sporadic MD.

Menière’s disease (MD) is an inner ear disorder characterised by episodes of vertigo, sensorineural hearing loss and tinnitus linked to autoinflammation and/or type 2 immune response. We hypothesise that rare variation in immune response genes could drive the autoinflammatory phenotype in MD. We retrieved differentially expressed genes (DEG) from single-cell RNAseq and epigenomic datasets to search for rare variants in the MD exome (N = 454) and genome (N = 511) sequencing datasets. The variant chr1:10374335 C > T in the KIF1B gene was found in three MD unrelated individuals and was predicted to be likely pathogenic. According to differential transcript usage, transcript ENST00000622724.3 was found in MD samples, but absent in controls. Furthermore, this variant may influence splicing through the generation of exonic enhancers and silencers, potentially changing transcription factor binding at the promoter. These findings support that this KIF1B gene rare variant is associated with the MD autoinflammatory phenotype and may up-regulate its expression in monocytes.

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.

Ménière disease (MD) is a complex inner ear disorder characterized by episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Despite its prevalence across European and Asian populations, along with five clinical subtypes with variable phenotypes and comorbidities, the molecular underpinnings of MD pathogenesis remain under investigation. This review aims to comprehensively summarize the genomic, epigenomic, and transcriptomic insights into MD, highlighting how these molecular layers contribute to disease susceptibility, progression, and phenotypic variability. Sporadic MD accounts for most diagnoses, where multifactorial mechanisms involving pathogenic rare variants, epigenetic modifications, and immune-related pathways contribute to disease risk. We also elucidate the genetic contribution of familial MD, in which inherited variants, primarily in genes involved in the extracellular structures of sensory epithelia and the stereocilia links of sensory cells, contribute to autosomal dominant, recessive, or digenic inheritance models. Furthermore, we explore the current use of animal models in validating gene pathogenicity. By integrating findings across multi-omics studies, this review emphasizes that MD is a polygenic and heterogeneous inherited disorder, with a spectrum of related conditions with common and distinct molecular origins. Understanding molecular mechanisms involving genetic and epigenetic factors is promising for biomarker discovery and future therapeutic interventions.