A Systems Biology Framework Uncovers Multi-Level Genetic Regulation of Dizziness/vertigo Through eQTL-GWAS Integration and Single-Cell Analysis.

BACKGROUND Dizziness/vertigo is a multifactorial neurological disorder with complex ge-netic and cellular bases, yet its molecular mechanisms remain unclear. Understanding how gene regulation contributes to dizziness/vertigo may reveal novel neurobiological and therapeutic insights.

METHODS We established a multi-omics integrative framework combining genome-wide association study (GWAS) data with expression quantitative trait loci (eQTL) from brain single-cell types, CD4+ T cells, oneK1K immune cells, and plasma. Two-sample Mendelian randomization (MR) and colocalization analyses were applied to identify causal genes. Single-cell RNA sequencing (scRNA-seq) of the auditory nerve was used to as-sess cell type-specific expression, intercellular communication, and pseudotime dynam-ics. Gene-gene interaction and drug-target networks were further constructed to identify potential therapeutic candidates.

RESULTS Six key genes-Activin A Receptor Type 2A (ACVR2A), Phospholipid Transfer Protein (PLTP), Androgen Dependent TFPI Regulating Protein (ADTRP), Methylenetetrahydrofolate Dehydrogenase (NADP + Dependent) 1 Like (MTHFD1L), Collagen Type VII Alpha 1 Chain (COL7A1), and Pantothenate Kinase 4 (PANK4)-showed strong causal and colocalization evidence for dizziness/vertigo. Single-cell analysis revealed distinct cell type-specific expression, with fibroblasts and adipocytes playing central roles in signaling and gene regulation. Pseudo-time trajectories indicated coordinated upregulation of ACVR2A, MTHFD1L, PANK4, and PLTP during later developmental stages. Interaction network analysis positioned these genes as major hubs, and DrugBank screening identified Sotatercept as a promising candidate targeting ACVR2A.

CONCLUSION This integrative analysis links gene expres-sion regulation to dizziness/vertigo across neuroimmune and metabolic systems. The findings uncover coordinated molecular pathways underlying disease susceptibility and highlight novel therapeutic targets, providing a foundation for precision treatment strate-gies.