Deciphering shared genetic architecture between migraine and intracranial aneurysm: an integrative genomic study of neurovascular comorbidity

Epidemiological studies have suggested an association between migraine and intracranial aneurysm (IA), but their shared genetic basis remains unclear. This study aimed to characterize the common genetic factors between the two disorders. Using genome-wide association study (GWAS) summary statistics for migraine and IA, we assessed genome-wide and local genetic correlations using linkage disequilibrium score regression (LDSC), high-definition likelihood (HDL), and SUPER GeNetic cOVariance Analyzer (SUPERGNOVA). Polygenic overlap was quantified with bivariate causal mixture modeling (MiXeR). Shared loci were identified through cross-trait meta-analysis and evaluated by Bayesian colocalization. Stratified LDSC, tissue enrichment, summary-data-based Mendelian randomization (SMR), transcriptome-wide association study (TWAS), and cell-type expression profiling were used to prioritize shared functional genes and pathways. Bidirectional Mendelian randomization (MR) with sensitivity analysis was performed to assess the directional relationship between the two traits. LDSC showed a significant positive genetic correlation between migraine and IA ( r g = 0.168, p = 0.0013). SUPERGNOVA identified significant local genetic correlation signals on chromosomes 16 and 18. MiXeR indicated a moderate genetic correlation ( r g = 0.23), with about 26% of causal variants overlapping between the two traits. Cross-trait meta-analysis identified six prioritized pleiotropic SNPs, four of which were functionally annotated for subsequent colocalization testing, while colocalization prioritized rs6046147, rs11646852, and rs11187838 as shared risk variants. SMR analysis identified BCAR1, CFDP1, and TMEM170A as shared functional genes, suggesting expression-mediated pleiotropic effects. Integrative TWAS followed by conditional analysis further prioritized FHL5 and TMEM170A as robust shared candidate genes. Arterial tissue enrichment and vascular-associated cell involvement were suggested. MR findings were sensitive to instrument selection, and complementary analyses did not support directional causality, favoring shared genetic liability or correlated pleiotropy. Migraine and IA share convergent genetic architecture, characterized by overlapping pleiotropic variants, prioritized functional genes, vascular-related tissue and cell-type signals. The MR results do not establish a directional causal relationship between the two disorders. These findings support partially shared genetic liability between migraine and IA and prioritize candidate loci and genes for further mechanistic investigation. Their tissue-level and clinical relevance requires independent functional and prospective validation.