A splice variant in the ACSL5 gene relates migraine with fatty acid activation in mitochondria

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/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 = 2x10(-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-Delta 20). 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-Delta 20 molecules, a mitochondrial located enzyme, is involved in migraine pathology.We thank the GEUVADIS Consortium for the RNA-Seq data and 1000 Genomes consortium for accessibility that permitted the analysis of our data. We thank Dr LR Desviat for kindly provide us the pSPL3 plasmid and suggestions. This work was supported by Fondo de Investigacion Sanitaria (FIS) Instituto de Salud Carlos III(ISCIII) Fondos Europeos de Desarrollo Regional (FEDER), Union Europea (grant numbers P12/00555 and PI13/01527) and Junta de Andalucia (JA)- Fondos Europeos de Desarrollo Regional (FEDER) (grant number CTS2704).Peer reviewe