Causal cross-trait mapping at single-cell resolution identifies shared immunogenetic drivers of migraine and Meniere's disease.

BACKGROUND

Migraine and Meniere’s disease (MD) show high clinical comorbidity, shared symptoms such as vertigo and overlapping mechanisms like neurogenic inflammation suggest common pathophysiology. However, the core immunogenetic drivers underlying this comorbidity, particularly at cellular resolution, remain uncharacterized.

METHODS

We integrated cross-trait genetic analyses using summary statistics from large genome-wide association study (GWAS) and single-cell expression quantitative trait locus (sc-eQTL), followed by Bayesian colocalization. Candidate genes were validated with independent single-cell RNA sequencing (scRNA-seq) and their therapeutic potential was assessed via drug repurposing and Phenome-wide association studies (PheWAS).

RESULTS

We identified a significant genetic correlation (rg = 0.226) and 4 high-confidence shared prioritized genes (cell division cycle 42 [CDC42], dicarbonyl and L-xylulose reductase [DCXR], GTP binding protein 4 [GTPBP4], sterol-c5-desaturase [SC5D]). Single-cell analyses confirmed their cell-type-specific dysregulation. Drug target interrogation identified existing pharmacological agents interacting with these genes, including Lorlatinib for CDC42. PheWAS highlighted distinct safety profiles for each target, informing future therapeutic development priorities.

CONCLUSIONS

This study reveals a shared immunogenetic basis between migraine and MD at single-cell resolution, providing novel targets and a translational roadmap for therapeutic development. CLINICAL TRIAL: Not applicable.