Integrative genomic and single-cell transcriptomic analyses suggest a putative zinc transport-immune axis in...

Meniere's disease is a disabling inner-ear disorder whose molecular basis remains poorly understood. Immune dysregulation and genetic susceptibility have been implicated in disease etiology, but the genes and immune-cell programs linking genetic susceptibility to disease-associated molecular alterations remain incompletely defined. Focusing on zinc transport and immune signaling, we aimed to prioritize genetically supported candidate genes and identify the immune-cell programs in which they are embedded.

We combined bulk peripheral blood transcriptomes, single-cell RNA sequencing of peripheral blood mononuclear cells, large-scale blood eQTL data, and genome-wide association summary statistics for Meniere's disease. Differential expression analysis and WGCNA were used to define bulk transcriptional signatures, which were then integrated with scRNA-seq-derived cell-type marker genes to generate a candidate-gene set with complementary bulk disease-association and cell-type localization evidence. Two-sample Mendelian randomization and colocalization were applied to test whether genetically predicted expression of these candidate genes influences Meniere's disease risk. Prioritized genes were then mapped to immune-cell subsets, ligand-receptor communication networks, and CD4⁺ T-cell differentiation trajectories at single-cell resolution, and their expression changes were validated at the mRNA and protein levels in an independent clinical cohort.

Bulk and single-cell analyses yielded 202 Meniere's disease-associated candidate genes enriched in RNA processing, chromatin regulation, and immune-related pathways. Two-sample Mendelian randomization identified nominal associations between genetically predicted expression of SLC39A10, GAB1, and XCL2 and Meniere's disease risk. Integration with bulk transcriptomic evidence prioritized increased SLC39A10 expression and reduced GAB1 and XCL2 expression for further analysis. Immune-signature enrichment and single-cell analyses localized their expression-related programs to CD4⁺ T cells, NK cells, monocytes, B cells, and other peripheral immune populations. CellChat and pseudotime analyses provided complementary descriptions of inferred intercellular communication and CD4⁺ T-cell state transitions. In an independent clinical cohort, SLC39A10, GAB1, and XCL2 showed concordant changes at the transcript and protein levels.

Our multi-layered genomic and single-cell analyses prioritize SLC39A10, GAB1, and XCL2 as candidate genes associated with Meniere's disease and map their expression-related programs to CD4⁺ T-cell, NK-cell, and other peripheral immune compartments. Together, these findings support a putative zinc transport-immune framework that may contribute to systemic immune dysregulation in Meniere's disease. This framework should be regarded as a hypothesis generated by integrative genomic and transcriptomic evidence and requires direct validation through measurements of zinc homeostasis, transporter activity, and downstream immune function.