Exploring the shared genetic architecture of migraine and autoimmune diseases

Migraine (MIG) frequently co-occurs with autoimmune diseases (ADs), but the shared genetic basis underlying this comorbidity remains unclear.

Using publicly available GWAS summary statistics from European populations, we applied an integrated framework to investigate the shared genetic architecture between MIG and seven ADs (SLE, UC, CD, PSC, T1D, RA, MS). Genetic correlations and polygenic overlap were evaluated using LDSC, HDL, and MiXeR. Shared pleiotropic loci were identified via PLACO and annotated with FUMA. Gene-level analyses were conducted using MAGMA, followed by PPI and pathway enrichment analyses. SMR was used to prioritize candidate genes. In addition, a PheWAS-guided Mendelian randomization framework and multi-trait colocalization analyses were performed.

MIG showed significant positive genetic correlations with SLE and UC, but a negative genetic correlation with PSC. Cross-trait pleiotropy analysis identified 22 shared loci across three MIG-AD pairs, of which 8 showed colocalization evidence. MAGMA identified 182 pleiotropic genes, with strongest convergence for MIG-UC. Enrichment analyses implicated blood- and immune-related tissues and highlighted receptor tyrosine kinase, endocytosis, axon guidance, gliogenesis, and PI3K/AKT signaling. SMR prioritized candidate genes including INPP5B and CARD9. PheWAS-guided MR identified seven MIG-associated phenotypes, whereas subsequent multi-trait colocalization did not detect robust shared causal variants.

MIG shares a selective and substantial genetic overlap with a subset of ADs, involving both immune-related and neurobiological mechanisms.