Shared genetic architecture between physical activity-related traits and migraine: evidence from integrative genomic and transcriptomic analyses

Physical activity (PA) and sedentary behavior have been linked to migraine, but their associations remain unclear due to potential confounding and migraine-related activity avoidance. We investigated the shared genetic architecture linking PA-related traits and migraine. Using genome-wide association study (GWAS) summary statistics for PA and migraine, we assessed global and local genetic correlations with linkage disequilibrium score regression and Local Analysis of [co]Variant Association. We first examined pleiotropic signals at the variant and locus levels, and then extended the analysis to the gene and transcriptomic levels using transcriptome-wide association study (TWAS), followed by summary-data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) testing. Finally, functional enrichment and latent causal variable analyses were further performed. Leisure screen time (LST) showed a positive genetic correlation with migraine, whereas other traits showed negative genetic correlations. We identified 103 genes with shared TWAS associations across PA–migraine pairs. Integrative analyses prioritized six LST–migraine genes, ABCB9, ARL6IP4, OGFOD2, PITPNM2, RILPL2, and SBNO1, while AKAP10 was the only moderate-to-vigorous physical activity (MVPA)–migraine gene detected in both brain and skeletal muscle tissues. TWAS-SMR integration identified 45 gene–tissue associations involving 22 genes for LST–migraine and prioritized ARL6IP4 and PITPNM2 after integration with COLOC-supported loci, with no evidence of HEIDI heterogeneity. Enrichment analyses implicated chemical stimulus detection and olfactory transduction, consistent with migraine-related sensory processing. These findings suggest that sedentary behavior and PA exhibit opposite genetic correlations with migraine. Prioritized genes implicate tissue-dependent neuro–muscular and sensory-related pathways, providing candidate targets for functional validation.