Genome-wide association studies (GWAS) in
migraine are providing the molecular basis of this heterogeneous disease, but the understanding of its aetiology is still incomplete. Although some
biomarkers have currently been accepted for
migraine, large amount of studies for identifying new ones is needed. The
migraine-associated variant rs12355831:A>G (
P=2 × 10-6), described in a GWAS of the International
Headache Genetic Consortium, is localized in a non-coding sequence with unknown function. We sought to identify the causal variant and the genetic mechanism involved in the
migraine risk. To this end, we integrated data of RNA sequences from the Genetic European Variation in Health and Disease (GEUVADIS) and genotypes from 1000 GENOMES of 344 lymphoblastoid cell lines (LCLs), to determine the expression quantitative trait loci (eQTLs) in the region. We found that the
migraine-associated variant belongs to a linkage disequilibrium block associated with the expression of an
acyl-coenzyme A synthetase 5 (ACSL5) transcript lacking exon 20 (ACSL5-Δ20). We showed by exon-skipping assay a direct causality of rs2256368-G in the exon 20 skipping of approximately 20 to 40% of ACSL5
RNA molecules. In conclusion, we identified the functional variant (rs2256368:A>G) affecting ACSL5 exon 20 skipping, as a causal factor linked to the
migraine-associated rs12355831:A>G, suggesting that the activation of long-chain
fatty acids by the spliced ACSL5-Δ20 molecules, a mitochondrial located
enzyme, is involved in
migraine pathology.