title: A splice variant in the ACSL5 gene relates migraine with fatty acid activation in mitochondria.
abstract: 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.
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Matesanz
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Fedetz
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barrionuevo
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Karaky
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Catalá-Rabasa
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.|Department of Computer Languages and Systems-CITIC, Universidad de Granada (UGR), Granada, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Potenciano
authors.affiliation: Departamento de Biología Molecular, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Bello-Morales
authors.affiliation: Departamento de Biología Molecular, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Jose-Antonio
authors.initials: JA
authors.lastname: López-Guerrero
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcina
mesh_terms: D003066:Coenzyme A Ligases / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005227:Fatty Acids / Q000378:metabolism; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D015810:Linkage Disequilibrium; D008881:Migraine Disorders / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D012326:RNA Splicing; D017384:Sequence Deletion
chemical_list: D005227:Fatty Acids; D003066:Coenzyme A Ligases; C485465:ACSL5 protein, human