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A review of migraine genetics: gathering genomic and transcriptomic factors

Abstract

Migraine is a common and complex neurologic disorder that affects approximately 15–18% of the general population. Although the cause of migraine is unknown, some genetic studies have focused on unravelling rare and common variants underlying the pathophysiological mechanisms of this disorder. This review covers the advances in the last decade on migraine genetics, throughout the history of genetic methodologies used, including recent application of next-generation sequencing techniques. A thorough review of the literature interweaves the genomic and transcriptomic factors that will allow a better understanding of the mechanisms underlying migraine pathophysiology, concluding with the clinical utility landscape of genetic information and future consideration to creating a new frontier toward advancing the field of personalized medicine.

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References

  1. Allan W (1928) The inheritance of migraine. Arch Intern Med 42(4):590–599. https://doi.org/10.1001/archinte.1928.00130210138013

    Article  Google Scholar 

  2. Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS, Nyholt DR, Dimas AS, Freilinger T, Müller-Myhsok B, Artto V, Inouye M, Alakurtti K, Kaunisto MA, Hämäläinen E, De Vries B, Stam AH, Weller CM, Heinze A, Palotie A (2010) Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet 42(10):869–873. https://doi.org/10.1038/ng.652

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, Kallela M, Malik R, De Vries B, Terwindt G, Medland SE, Todt U, McArdle WL, Quaye L, Koiranen M, Ikram M, Lehtimäki T, Stam AH, Ligthart L, Palotie A (2013) Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet 45(8):912–917. https://doi.org/10.1038/ng.2676

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Arndt AK, Schafer S, Drenckhahn JD, Sabeh MK, Plovie ER, Caliebe A, Klopocki E, Musso G, Werdich AA, Kalwa H, Heinig M, Padera RF, Wassilew K, Bluhm J, Harnack C, Martitz J, Barton PJ, Greutmann M, Berger F, Klaassen S (2013) Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy. Am J Hum Genet 93(1):67–77. https://doi.org/10.1016/j.ajhg.2013.05.015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Atkinson AJ, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, Hoth DF, Oates JA, Peck CC, Schooley RT, Spilker BA, Woodcock J, Zeger SL (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95. https://doi.org/10.1067/mcp.2001.113989

    Article  Google Scholar 

  6. Bertier G, Hétu M, Joly Y (2016) Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views Donna Dickenson, Sandra Soo-Jin Lee, and Michael Morrison. BMC Med Genomics. https://doi.org/10.1186/s12920-016-0213-6

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bron C, Sutherland HG, Griffiths LR (2021) Exploring the hereditary nature of migraine. Neuropsychiatr Dis Treat 17:1183–1194. https://doi.org/10.2147/NDT.S282562

    Article  PubMed  PubMed Central  Google Scholar 

  8. Burstein R, Noseda R, Borsook D (2015) Migraine: multiple processes, complex pathophysiology. J Neurosci 35(17):6619–6629. https://doi.org/10.1523/JNEUROSCI.0373-15.2015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, Serrano D, Lipton RB (2013) Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine prevalence and prevention (AMPP) study. Headache 53(8):1278–1299. https://doi.org/10.1111/head.12150

    Article  PubMed  Google Scholar 

  10. Cano-Gamez E, Trynka G (2020) From GWAS to function: using functional genomics to identify the mechanisms underlying complex diseases. Front Genet 11:1–21. https://doi.org/10.3389/fgene.2020.00424

    CAS  Article  Google Scholar 

  11. Capi M, Gentile G, Lionetto L, Salerno G, Cipolla F, Curto M, Borro M, Martelletti P (2018) Pharmacogenetic considerations for migraine therapies. Expert Opin Drug Metab Toxicol 14(11):1161–1167. https://doi.org/10.1080/17425255.2018.1541452 (Taylor and Francis Ltd)

    CAS  Article  PubMed  Google Scholar 

  12. Chalmer MA, Esserlind AL, Olesen J, Hansen TF (2018) Polygenic risk score: use in migraine research. J Headache Pain. https://doi.org/10.1186/s10194-018-0856-0

    Article  PubMed  PubMed Central  Google Scholar 

  13. Charles A (2018a) The pathophysiology of migraine: implications for clinical management. Lancet Neurol 17(2):174–182. https://doi.org/10.1016/S1474-4422(17)30435-0 (Lancet Publishing Group)

    CAS  Article  PubMed  Google Scholar 

  14. Charles A (2018b) The migraine aura. CONTINUUM Lifelong Learn Neurol 24(4-Headache):1009–1022. https://doi.org/10.1212/CON.0000000000000627 (Lippincott Williams and Wilkins)

    Article  Google Scholar 

  15. Chasman DI, Schürks M, Anttila V, De Vries B, Schminke U, Launer LJ, Terwindt GM, Van Den Maagdenberg AMJM, Fendrich K, Völzke H, Ernst F, Griffiths LR, Buring JE, Kallela M, Freilinger T, Kubisch C, Ridker PM, Palotie A, Ferrari MD, Kurth T (2011) Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 43(7):695–698. https://doi.org/10.1038/ng.856

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Costa C, Tozzi A, Rainero I, Cupini LM, Calabresi P, Ayata C, Sarchielli P (2013) Cortical spreading depression as a target for anti-migraine agents. J Headache Pain 14(1):1–18. https://doi.org/10.1186/1129-2377-14-62

    Article  Google Scholar 

  17. Craps S, Van Wauwe J, De Moudt S, De Munck D, Leloup AJA, Boeckx B, Vervliet T, Dheedene W, Criem N, Geeroms C, Jones EAV, Zwijsen A, Lambrechts D, Fransen P, Beerens M, Luttun A (2021) Prdm16 supports arterial flow recovery by maintaining endothelial function. Circ Res 129(1):63–77. https://doi.org/10.1161/CIRCRESAHA.120.318501

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. de Boer I, Terwindt GM, van den Maagdenberg AMJM (2020) Genetics of migraine aura: an update. J Headache Pain 21(1):64. https://doi.org/10.1186/s10194-020-01125-2

    Article  PubMed  PubMed Central  Google Scholar 

  19. de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AMJM (2009) Molecular genetics of migraine. Hum Genet 126(1):115–132. https://doi.org/10.1007/s00439-009-0684-z

    CAS  Article  PubMed  Google Scholar 

  20. De Vries B, Anttila V, Freilinger T, Wessman M, Kaunisto MA, Kallela M, Artto V, Vijfhuizen LS, Göbel H, Dichgans M, Kubisch C, Ferrari MD, Palotie A, Terwindt GM, Van Den Maagdenberg AMJM (2016) Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set. Cephalalgia 36(7):604–614. https://doi.org/10.1177/0333102414566820

    Article  PubMed  Google Scholar 

  21. Di Lorenzo C, Grieco GS, Santorelli FM (2012) Migraine headache: a review of the molecular genetics of a common disorder. J Headache Pain 13(7):571–580. https://doi.org/10.1007/s10194-012-0478-x

    Article  PubMed  PubMed Central  Google Scholar 

  22. Edvinsson L, Haanes KA, Warfvinge K, Di Krause N (2018a) CGRP as the target of new migraine therapies—successful translation from bench to clinic. Nat Rev Neurol 14(6):338–350. https://doi.org/10.1038/s41582-018-0003-1 (Nature Publishing Group)

    CAS  Article  PubMed  Google Scholar 

  23. Edvinsson L, Tajti J, Szalárdy L, Vécsei L (2018b) PACAP and its role in primary headaches. J Headache Pain. https://doi.org/10.1186/s10194-018-0852-4

    Article  PubMed  PubMed Central  Google Scholar 

  24. Esserlind AL, Christensen AF, Steinberg S, Grarup N, Pedersen O, Hansen T, Werge T, Hansen TF, Husemoen LLN, Linneberg A, Budtz-Jorgensen E, Westergaard ML, Stefansson H, Olesen J (2016) The association between candidate migraine susceptibility loci and severe migraine phenotype in a clinical sample. Cephalalgia 36(7):615–623. https://doi.org/10.1177/0333102415570492

    Article  PubMed  Google Scholar 

  25. Freilinger T, Anttila V, De Vries B, Malik R, Kallela M, Terwindt GM, Pozo-Rosich P, Winsvold B, Nyholt DR, Van Oosterhout WPJ, Artto V, Todt U, Hämäläinen E, Fernández-Morales J, Louter MA, Kaunisto MA, Schoenen J, Raitakari O, Lehtimäki T, Van Den Maagdenberg AMJM (2012) Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet 44(7):777–782. https://doi.org/10.1038/ng.2307

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Gasparini C, Sutherland H, Griffiths L (2013) Studies on the pathophysiology and genetic basis of migraine. Curr Genomics 14(5):300–315. https://doi.org/10.2174/13892029113149990007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Gazerani P (2019) Current evidence on potential uses of MicroRNA biomarkers for migraine: from diagnosis to treatment. Mol Diagn Ther 23(6):681–694. https://doi.org/10.1007/s40291-019-00428-8

    CAS  Article  PubMed  Google Scholar 

  28. Gazerani P, Vinterhøj HSH (2016) “Omics”: an emerging field in pain research and management. Fut Neurol 11(4):255–265. https://doi.org/10.2217/fnl-2016-0018 (Future Medicine Ltd)

    CAS  Article  Google Scholar 

  29. Gerring Z, Rodriguez-Acevedo AJ, Powell JE, Griffiths LR, Montgomery GW, Nyholt DR (2016) Blood gene expression studies in migraine: potential and caveats. Cephalalgia 36(7):669–678. https://doi.org/10.1177/0333102416628463

    Article  PubMed  Google Scholar 

  30. Gerring ZF, Powell JE, Montgomery GW, Nyholt DR (2018) Genome-wide analysis of blood gene expression in migraine implicates immune-inflammatory pathways. Cephalalgia 38(2):292–303. https://doi.org/10.1177/0333102416686769

    Article  PubMed  Google Scholar 

  31. Gervil M, Ulrich V, Kaprio J, Olesen J, Russell MB (1999) The relative role of genetic and environmental factors in migraine without aura. Neurology 53(5):995–999. https://doi.org/10.1212/wnl.53.5.995

    CAS  Article  PubMed  Google Scholar 

  32. Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF, Olesen J, Altman J, Goadsby PJ, Macrae A (2003) Premonitory symptoms in migraine: an electronic diary study. Neurology 60(6):935–940. https://doi.org/10.1212/01.WNL.0000052998.58526.A9

    CAS  Article  PubMed  Google Scholar 

  33. Giffin NJ, Lipton RB, Silberstein SD, Olesen J, Goadsby PJ (2016) The migraine postdrome: an electronic diary study. Neurology. https://doi.org/10.1212/WNL.0000000000002789

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, Pers TH, Farh KH, Cuenca-Leon E, Muona M, Furlotte NA, Kurth T, Ingason A, McMahon G, Ligthart L, Terwindt GM, Kallela M, Freilinger TM, Ran C, Gordon SG, Zhao H (2016a) Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 48(8):856–866. https://doi.org/10.1038/ng.3598

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Gormley P, Winsvold BS, Nyholt DR, Kallela M, Chasman DI, Palotie A (2016b) Migraine genetics: from genome-wide association studies to translational insights. Genome Med 8(1):86. https://doi.org/10.1186/s13073-016-0346-4

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gormley P, Kurki M, Hiekkala ME, Veerapen K, Häppölä P, Mitchell AA, Lal D, Palta P, Surakka I, Kaunisto M, Hämäläinen E, Vepsäläinen S, Havanka H, Harno H, Ilmavirta M, Nissilä M, Säkö E, Sumelahti ML, Liukkonen J, Ripatti S (2018) Common variant burden contributes to the familial aggregation of migraine in 1,589 families. Neuron 98(4):743-753.e4. https://doi.org/10.1016/j.neuron.2018.04.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Guo Y, Rist PM, Daghlas I, Giulianini F, Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, Pers TH, Farh KH, Cuenca-Leon E, Muona M, Furlotte NA, Kurth T, Ingason A, McMahon G, Ligthart L, Terwindt GM, Chasman DI (2020) A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine. Nat Commun 11(1):1–11. https://doi.org/10.1038/s41467-020-17002-0

    CAS  Article  Google Scholar 

  38. Gupta RM, Hadaya J, Trehan A, Zekavat SM, Roselli C, Klarin D, Emdin CA, Hilvering CRE, Bianchi V, Mueller C, Khera AV, Ryan RJH, Engreitz JM, Issner R, Shoresh N, Epstein CB, de Laat W, Brown JD, Schnabel RB, Kathiresan S (2017) A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170(3):522-533.e15. https://doi.org/10.1016/j.cell.2017.06.049

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Hautakangas H, Winsvold BS, Ruotsalainen SE, Bjornsdottir G, Harder AVE, Kogelman LJA, Thomas LF, Noordam R, Benner C, Gormley P, Artto V, Banasik K, Bjornsdottir A, Boomsma DI, Brumpton BM, Burgdorf KS, Buring JE, Chalmer MA, de Boer I, Pirinen M (2021) Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. MedRxiv. https://doi.org/10.1101/2021.01.20.21249647

    Article  Google Scholar 

  40. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition (2018) The international classification of headache disorders, (beta version). Cephalalgia Int J Headache 38(1):1–211. https://doi.org/10.1177/0333102417738202

    Article  Google Scholar 

  41. Hoffmann J, Baca SM, Akerman S (2019) Neurovascular mechanisms of migraine and cluster headache. J Cereb Blood Flow Metab 39(4):573–594. https://doi.org/10.1177/0271678X17733655 (SAGE Publications Ltd)

    Article  PubMed  Google Scholar 

  42. Honkasalo M-L, Kaprio J, Winter T, Heikkilä K, Sillanpää M, Koskenvuo M (1995) Migraine and concomitant symptoms among 8167 adult twin pairs. Headache J Head Face Pain 35(2):70–78. https://doi.org/10.1111/j.1526-4610.1995.hed3502070.x

    CAS  Article  Google Scholar 

  43. Ibrahim O, Sutherland HG, Maksemous N, Smith R, Haupt LM, Griffiths LR (2020) Exploring neuronal vulnerability to head trauma using a whole exome approach. J Neurotrauma. https://doi.org/10.1089/neu.2019.6962

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ivic I, Balasko M, Fulop BD, Hashimoto H, Toth G, Tamas A, Juhasz T, Koller A, Reglodi D, Solymár M (2019) VPAC1 receptors play a dominant role in PACAP-induced vasorelaxation in female mice. PLoS ONE. https://doi.org/10.1371/journal.pone.0211433

    Article  PubMed  PubMed Central  Google Scholar 

  45. Jensen R, Stovner LJ (2008) Epidemiology and comorbidity of headache. Lancet Neurol 7(4):354–361. https://doi.org/10.1016/S1474-4422(08)70062-0

    Article  PubMed  Google Scholar 

  46. Jeong H, Moye LS, Southey BR, Hernandez AG, Dripps I, Romanova EV, Rubakhin SS, Sweedler JV, Pradhan AA, Rodriguez-Zas SL (2018) Gene network dysregulation in the trigeminal ganglia and nucleus accumbens of a model of chronic migraine-associated hyperalgesia. Front Syst Neurosci 12:1–19. https://doi.org/10.3389/fnsys.2018.00063

    CAS  Article  Google Scholar 

  47. Karsan N, Bose P, Goadsby PJ (2018) The migraine premonitory phase. In CONTINUUM Lifelong Learn Neurol 24(4-Headache):996–1008. https://doi.org/10.1212/CON.0000000000000624 (Lippincott Williams and Wilkins)

    Article  Google Scholar 

  48. Kogelman LJA, Esserlind A-L, Francke Christensen A, Awasthi S, Ripke S, Ingason A, Davidsson OB, Erikstrup C, Hjalgrim H, Ullum H, Olesen J, Folkmann Hansen T (2019a) Migraine polygenic risk score associates with efficacy of migraine-specific drugs. Neurol Genet 5(6):e364. https://doi.org/10.1212/nxg.0000000000000364

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kogelman LJA, Falkenberg K, Halldorsson GH, Poulsen LU, Worm J, Ingason A, Stefansson H, Stefansson K, Hansen TF, Olesen J (2019b) Comparing migraine with and without aura to healthy controls using RNA sequencing. Cephalalgia 39(11):1435–1444. https://doi.org/10.1177/0333102419851812

    Article  PubMed  Google Scholar 

  50. Kogelman LJA, Falkenberg K, Buil A, Erola P, Courraud J, Laursen SS, Michoel T, Olesen J, Hansen TF (2020) Changes in the gene expression profile during spontaneous migraine attacks. BioRxiv. https://doi.org/10.1101/000042

    Article  Google Scholar 

  51. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, MacArthur DG (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291. https://doi.org/10.1038/nature19057

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Lemos C, Castro MJ, Barros J, Sequeiros J, Pereira-Monteiro J, Mendonça D, Sousa A (2009) Familial clustering of migraine: Further evidence from a portuguese study. Headache 49(3):404–411. https://doi.org/10.1111/j.1526-4610.2008.01177.x

    Article  PubMed  Google Scholar 

  53. Leo AAP (1944) Spreading depression of activity in the cerebral cortex. J Neurophysiol 7(6):359–390. https://doi.org/10.1152/jn.1944.7.6.359

    Article  Google Scholar 

  54. Malhotra R (2016) Understanding migraine: Potential role of neurogenic inflammation. Ann Indian Acad Neurol 19(2):175–182. https://doi.org/10.4103/0972-2327.182302

    Article  PubMed  PubMed Central  Google Scholar 

  55. May A, Goadsby PJ (2001) Substance P receptor antagonists in the therapy of migraine. Expert Opin Investig Drugs 10(4):673–678. https://doi.org/10.1517/13543784.10.4.673

    CAS  Article  PubMed  Google Scholar 

  56. Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, Hölttä M, Rosén C, Olsson C, Strobel G, Wu E, Dakin K, Petzold M, Blennow K, Zetterberg H (2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15(7):673–684. https://doi.org/10.1016/S1474-4422(16)00070-3

    CAS  Article  PubMed  Google Scholar 

  57. Peden JF, Hopewell JC, Saleheen D, Chambers JC, Hager J, Soranzo N, Collins R, Danesh J, Elliott P, Farrall M, Stirrups K, Zhang W, Hamsten A, Parish S, Lathrop M, Watkins H, Clarke R, Deloukas P, Kooner JS, Anand SS (2011) A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 43(4):339–344. https://doi.org/10.1038/ng.782

    CAS  Article  Google Scholar 

  58. Pelzer N, Louter MA, van Zwet EW, Nyholt DR, Ferrari MD, van den Maagdenberg AMJM, Haan J, Terwindt GM (2019) Linking migraine frequency with family history of migraine. Cephalalgia 39(2):229–236. https://doi.org/10.1177/0333102418783295

    Article  PubMed  Google Scholar 

  59. Perry CJ, Blake P, Buettner C, Papavassiliou E, Schain AJ, Bhasin MK, Burstein R (2016) Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: implications for extracranial origin of headache. Ann Neurol 79(6):1000–1013. https://doi.org/10.1002/ana.24665

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Pietrobon D (2018) Ion channels in migraine disorders. Curr Opin Physiol 2:98–108. https://doi.org/10.1016/j.cophys.2018.02.001 (Elsevier Ltd)

    Article  Google Scholar 

  61. Pomes LM, Guglielmetti M, Bertamino E, Simmaco M, Borro M, Martelletti P (2019) Optimising migraine treatment: from drug-drug interactions to personalized medicine. J Headache Pain. https://doi.org/10.1186/s10194-019-1010-3

    Article  PubMed  PubMed Central  Google Scholar 

  62. Quintana S, Genovese A, Rausa F, Manzoni GC, Torelli P (2018) Migraine with typical aura: clinical features and their relationship with sex and age of onset. Results from the analysis of a large case series. Neurol Sci 39:135–136. https://doi.org/10.1007/s10072-018-3370-x

    Article  PubMed  Google Scholar 

  63. Ramachandran R (2018) Neurogenic inflammation and its role in migraine. Semin Immunopathol 40(3):301–314. https://doi.org/10.1007/s00281-018-0676-y (Springer)

    CAS  Article  PubMed  Google Scholar 

  64. Rasmussen AH, Kogelman LJA, Kristensen DM, Chalmer MA, Olesen J, Hansen TF (2020a) Functional gene networks reveal distinct mechanisms segregating in migraine families. Brain J Neurol 143(10):2945–2956. https://doi.org/10.1093/brain/awaa242

    Article  Google Scholar 

  65. Rasmussen AH, Olofsson I, Chalmer MA, Olesen J, Hansen TF (2020b) Higher burden of rare frameshift indels in genes related to synaptic transmission separate familial hemiplegic migraine from common types of migraine. J Med Genet 57(9):610–616. https://doi.org/10.1136/jmedgenet-2019-106640

    CAS  Article  PubMed  Google Scholar 

  66. Renthal W (2018) Localization of migraine susceptibility genes in human brain by single-cell RNA sequencing. Cephalalgia 38(13):1976–1983. https://doi.org/10.1177/0333102418762476

    Article  PubMed  Google Scholar 

  67. Royal P, Andres-Bilbe A, Ávalos Prado P, Verkest C, Wdziekonski B, Schaub S, Baron A, Lesage F, Gasull X, Levitz J, Sandoz G (2019) Migraine-associated TRESK mutations increase neuronal excitability through alternative translation initiation and inhibition of TREK. Neuron 101(2):232-245.e6. https://doi.org/10.1016/j.neuron.2018.11.039

    CAS  Article  PubMed  Google Scholar 

  68. Russell MB, Iselius L, Olesen J (1995) Inheritance of migraine investigated by complex segregation analysis. Hum Genet 96(6):726–730. https://doi.org/10.1007/BF00210307

    CAS  Article  PubMed  Google Scholar 

  69. Russo L, Mariotti P, Sangiorgi E, Giordano T, Ricci I, Lupi F, Chiera R, Guzzetta F, Neri G, Gurrieri F (2005) A new susceptibility locus for migraine with aura in the 15q11-q13 genomic region containing three GABA-A receptor genes. Am J Hum Genet 76(2):327–333. https://doi.org/10.1086/427521

    CAS  Article  PubMed  Google Scholar 

  70. Santiago JA, Bottero V, Potashkin JA (2018) Evaluation of RNA blood biomarkers in the Parkinson’s disease biomarkers program. Front Aging Neurosci 10:1–8. https://doi.org/10.3389/fnagi.2018.00157

    CAS  Article  Google Scholar 

  71. Schaid DJ, Chen W, Larson NB (2018) From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet 19(8):491–504. https://doi.org/10.1038/s41576-018-0016-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, Preuss M, Stewart AFR, Barbalic M, Gieger C, Absher D, Aherrahrou Z, Allayee H, Altshuler D, Anand SS, Andersen K, Anderson JL, Ardissino D, Ball SG, Erdmann J (2011) Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43(4):333–338. https://doi.org/10.1038/ng.784

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Serrano D, Manack AN, Reed ML, Buse DC, Varon SF, Lipton RB (2013) Cost and predictors of lost productive time in chronic migraine and episodic migraine: results from the american migraine prevalence and prevention (AMPP) study. Value Health 16(1):31–38. https://doi.org/10.1016/J.JVAL.2012.08.2212

    Article  PubMed  Google Scholar 

  74. Shademan BC, Avci B, Masoud N, Nourazarian A (2017) Application of next-generation sequencing in neurodegenerative diseases: opportunities and challenges. NeuroMolecular Med. https://doi.org/10.1007/s12017-020-08601-7

    Article  Google Scholar 

  75. Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81(3):1065–1096. https://doi.org/10.1152/physrev.2001.81.3.1065 (American Physiological Society)

    CAS  Article  PubMed  Google Scholar 

  76. Stewart WF, Bigal ME, Kolodner K, Dowson A, Liberman JN, Lipton RB (2006) Familial risk of migraine: variation by proband age at onset and headache severity. Neurology 66(3):344–348. https://doi.org/10.1212/01.wnl.0000196640.71600.00

    CAS  Article  PubMed  Google Scholar 

  77. Stovner LJ, Hagen K, Jensen R, Katsarava Z, Lipton RB, Scher AI, Steiner TJ, Zwart JA (2007) The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27(3):193–210. https://doi.org/10.1111/j.1468-2982.2007.01288.x

    Article  Google Scholar 

  78. Su L, Lei X, Ma H, Feng C, Jiang J, Jiao J (2020) PRDM16 orchestrates angiogenesis via neural differentiation in the developing brain. Cell Death Differ 27(8):2313–2329. https://doi.org/10.1038/s41418-020-0504-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Sun XY, Zhang J, Niu W, Guo W, Song HT, Li HY, Fan HM, Zhao L, Zhong AF, Dai YH, Guo ZM, Zhang LY, Lu J, Zhang QL (2015) A preliminary analysis of microRNA as potential clinical biomarker for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 168(3):170–178. https://doi.org/10.1002/ajmg.b.32292

    CAS  Article  Google Scholar 

  80. Sutherland HG, Griffiths LR (2017) Genetics of migraine: insights into the molecular basis of migraine disorders. Headache 57(4):537–569. https://doi.org/10.1111/head.13053 (Blackwell Publishing Inc)

    Article  PubMed  Google Scholar 

  81. Sutherland HG, Albury CL, Griffiths LR (2019) Advances in genetics of migraine. J Headache Pain. https://doi.org/10.1186/s10194-019-1017-9

    Article  PubMed  PubMed Central  Google Scholar 

  82. Tafuri E, Santovito D, De Nardis V, Marcantonio P, Paganelli C, Affaitati G, Bucci M, Mezzetti A, Giamberardino MA, Cipollone F (2015) MicroRNA profiling in migraine without aura: pilot study. Ann Med 47(6):468–473. https://doi.org/10.3109/07853890.2015.1071871

    CAS  Article  PubMed  Google Scholar 

  83. Tolner EA, Houben T, Terwindt GM, De Vries B, Ferrari MD, Van Den Maagdenberg AMJM (2015) From migraine genes to mechanisms. Pain 156(4):S64–S74. https://doi.org/10.1097/01.j.pain.0000460346.00213.16 (Lippincott Williams and Wilkins)

    Article  PubMed  Google Scholar 

  84. Ulrich V, Gervil M, Kyvik KO, Olesen J, Russell MB (1999) Evidence of a genetic factor in migraine with aura: a population-based Danish twin study. Ann Neurol 45(2):242–246. https://doi.org/10.1002/1531-8249(199902)45:2%3c242::AID-ANA15%3e3.0.CO;2-1

    CAS  Article  PubMed  Google Scholar 

  85. Van Den Maagdenberg AMJM, Nyholt DR, Anttila V (2019) Novel hypotheses emerging from GWAS in migraine? J Headache Pain. https://doi.org/10.1186/s10194-018-0956-x

    Article  PubMed  PubMed Central  Google Scholar 

  86. Van Dongen RM, Zielman R, Noga M, Dekkers OM, Hankemeier T, Mjm Van Den Maagdenberg A, Terwindt GM, Ferrari MD (2017) Migraine biomarkers in cerebrospinal fluid: a systematic review and meta-analysis. Cephalalgia. https://doi.org/10.1177/0333102415625614

    Article  PubMed  Google Scholar 

  87. Vaz-Drago R, Custódio N, Carmo-Fonseca M (2017) Deep intronic mutations and human disease. Hum Genet 136(9):1093–1111. https://doi.org/10.1007/s00439-017-1809-4

    CAS  Article  PubMed  Google Scholar 

  88. Vgontzas A, Renthal W (2020) Migraine-associated gene expression in cell types of the central and peripheral nervous system. Cephalalgia 40(5):517–523. https://doi.org/10.1177/0333102419877834

    Article  PubMed  Google Scholar 

  89. Viana M, Terrazzino S, Genazzani AA, Grieco GS, Cargnin S, Santorelli FM, Pierelli F, Tassorelli C, Nappi G, Di Lorenzo C (2014) Pharmacogenomics of episodic migraine: time has come for a step forward. Pharmacogenomics 15(4):541–549. https://doi.org/10.2217/pgs.14.20

    CAS  Article  PubMed  Google Scholar 

  90. Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, Abdulkader RS, Abdulle AM, Abebo TA, Abera SF, Aboyans V, Abu-Raddad LJ, Ackerman IN, Adamu AA, Adetokunboh O, Afarideh M, Afshin A, Agarwal SK, Aggarwal R, Murray CJL (2017) Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390(10100):1211–1259. https://doi.org/10.1016/S0140-6736(17)32154-2

    Article  Google Scholar 

  91. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10(1):57–63. https://doi.org/10.1038/nrg2484

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Williams LB, Javed A, Sabri A, Morgan DJ, Huff CD, Grigg JR, Heng XT, Khng AJ, Hollink IHIM, Morrison MA, Owen LA, Anderson K, Kinard K, Greenlees R, Novacic D, Nida Sen H, Zein WM, Rodgers GM, Vitale AT, DeAngelis MM (2019) ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. Genet Med 21(9):2103–2115. https://doi.org/10.1038/s41436-019-0476-3

    Article  PubMed  PubMed Central  Google Scholar 

  93. Zhang F, Lupski JR (2015) Non-coding genetic variants in human disease. Hum Mol Genet 24(R1):R102–R110. https://doi.org/10.1093/hmg/ddv259 (Oxford University Press)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Zhang XC, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R (2010) Activation of meningeal nociceptors by cortical spreading depression: Implications for migraine with aura. J Neurosci 30(26):8807–8814. https://doi.org/10.1523/JNEUROSCI.0511-10.2010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to acknowledge Professor Pereira-Monteiro who passed away this year. He was a very well-known neurologist and one of the leading national headache specialists and his reputation in this area extends internationally. We worked with Professor Pereira-Monteiro within the last 20 years and his clinical contribution was fundamental.

Funding

FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Cooperation Programme Interreg V-A Spain–Portugal under project ‘Análisis y correlación entre la epigenética y la actividad cerebral para evaluar el riesgo de migraña crónica y episódica en mujeres’ POCTEP 2014–2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER- 029486 (PTDC/MEC-NEU/29486/2017). AD is recipient of an FCT fellowship [SFRH/BD/136954/2018]. This research was also funded by Sociedade Portuguesa de Cefaleias (SPC) and Novartis.

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AD, TM, and MAF wrote the manuscript or figures. MAF, AS and CL were responsible for critical revision of the manuscript for important intellectual content.

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Correspondence to Miguel Alves-Ferreira.

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AD has received research support from an FCT fellowship (SFRH/BD/136954/2018). MAF is supported by a Junior Researcher contract of the project POCI-01-0145-FEDER- 029486 (PTDC/MEC-NEU/29486/2017). TM, AS and CL report no disclosures.

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Dias, A., Mariz, T., Sousa, A. et al. A review of migraine genetics: gathering genomic and transcriptomic factors. Hum Genet (2021). https://doi.org/10.1007/s00439-021-02389-7

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