Mapping the brain cell–specific regulatory architecture of migraine: a single-cell causal framework nominating inhibitory-neuronal BTBD16 and astrocytic RIMS1 as therapeutic targets

BACKGROUND: Migraine is a common, disabling neurological disorder. Genome-wide association studies have mapped numerous migraine risk loci, but the causal genes and their cell-type context remain unclear. Prior work linked migraine GWAS to bulk brain eQTLs; however, tissue-average signals obscure cell-specific regulation. METHODS: We extended these findings to single-cell resolution. Cis-eQTL instruments from 183 human donors across eight brain cell types were filtered by genome-wide significance, LD pruning, and instrument strength, yielding 1,746 independent eGenes. Two-sample Mendelian randomization (MR) tested effects on migraine risk in FinnGen R12 (discovery) with replication in UK Biobank (GCST90473326). To control for multiple testing, we applied within-cell-type Bonferroni correction and global false discovery rate (FDR) adjustment. Bayesian colocalization was performed in both discovery and replication cohorts to evaluate shared causal variants. We also performed a phenome-wide association screen (PheWAS) and profiled regional brain RNA. RESULTS: Eleven eGenes were significant in FinnGen. Protective associations were observed for BTBD16 in excitatory and inhibitory neurons, RRP15 in excitatory neurons, CCDC146 and GSTM3 in oligodendrocytes, and PDE4B in microglia. Risk-increasing associations were found for GSTM2 (excitatory neurons), RIMS1 and DPH1 (astrocytes), AADAC (microglia), and RBM20 (endothelium). Replication supported signals for inhibitory-neuronal BTBD16 and astrocytic RIMS1. Colocalization analyses indicated shared causal variants at both loci in the discovery cohort (PP.H4 > 0.80). PheWAS showed no genome-wide liabilities for either gene. Regional expression suggested white-matter enrichment for BTBD16 and a cerebellar peak for RIMS1. CONCLUSIONS: Cell-type-specific MR sharpens migraine mechanisms beyond bulk tissue and prioritizes inhibitory-neuronal BTBD16 (protective) and astrocytic RIMS1 (risk-increasing) for mechanistic validation and therapeutic exploration.