Migraine is the world’s most common neurological disorder, affecting ~14% of the adult population. The largest migraine GWAS comprising 102,084 migraine cases and 771,257 controls identified 170 independent genetic risk variants (SNPs) associated with migraine (P < 5×10-8). However, the functional mechanisms of these SNPs remain unclear.
Increasing evidence has demonstrated that alternative splicing can be modulated by heritable genetic variants (splice QTL [sQTL]). Identification of sQTLs could help to gain insight into the mechanisms underlying GWAS associations. In this study, we applied an imputation-based splicing transcriptome-wide association study (spTWAS) framework that integrates GWAS summary statistics with sQTLs to identify genetically regulated alternative splicing events associated with migraine.
We implemented summary-based MultiXcan across 49 GTEx tissues, to impute splicing variation into 143,979 introns. Of these, 4,182 introns demonstrated significant association with migraine at a Benjamini–Hochberg false discovery rate (FDR) < 0.05. To assess shared genetic architecture, we performed colocalisation analysis using COLOC, testing whether the same causal variant underlies both the sQTL and migraine GWAS signal. COLOC identified 767 introns (mapping to 392 genes) with strong evidence of colocalisation (posterior probability for a shared causal variant, PP4 > 0.5). Of these, 144 genes were present at an existing migraine risk loci and 248 genes reside >1 Mb from known migraine index SNPs, suggesting novel loci contributing to migraine susceptibility via alternate splicing.
This preliminary analysis highlights the utility of using sQTLs to decipher migraine GWAS. Future directions include conducting isoform-level TWAS (isoTWAS) to evaluate genetically regulated isoform abundance and its association with migraine risk. To our knowledge, this will represent the first comprehensive study integrating splicing and isoform-level transcriptomic regulation to elucidate migraine pathophysiology.