{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:10:50Z","timestamp":1789117850406,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: Migraine is a neurological disorder with a heterogeneous presentation; however, compounds perceived as effective by migraine sufferers are often underrepresented in research. This study adopts a novel exploratory approach to determine whether pharmacodynamic data from such compounds can be used to prioritise candidate migraine-related genes and biological pathways for future investigation, and to generate hypotheses regarding migraine pathophysiology. Methods: A structured internet search identified 181 compounds perceived as effective for migraine, of which 148 had at least one supportive report identified in the PubMed literature. Following DrugBank-based exclusions for insufficient interaction data, 137 compounds remained for analysis. A gene list was extrapolated from compound\u2013protein interactions, followed by analyses identifying significantly enriched tissues and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. Unique genes from enriched tissue-specific sublists were considered targets of interest, and those not previously directly associated with migraine in the databases and literature searches used were deemed candidate migraine target genes. Results: A total of 32 compounds affected the products of 21 targets of interest. CHRM3, CHRNA4, and SCN2B emerged as prioritised candidate genes that had not previously been directly associated with migraine in the databases examined. Enrichment analysis of the pharmacodynamically derived gene set identified tissue-enrichment signals involving skeletal muscle (q = 6.01 \u00d7 10\u22125), prefrontal cortex (q = 5.36 \u00d7 10\u22123), cerebellar peduncles (q = 1.28 \u00d7 10\u22122) and cerebellum (q = 4.79 \u00d7 10\u22122). Nine compounds interacting with established Familial Hemiplegic Migraine (FHM) genes may warrant future investigation. No conclusions regarding therapeutic efficacy are drawn from these data. Conclusions: This exploratory pipeline prioritised CHRM3, CHRNA4, and SCN2B as candidate genes for further investigation, alongside enriched tissues and pathways. These findings should be regarded as hypothesis-generating rather than evidence of causality or therapeutic utility. More broadly, variations of this prioritisation framework may prove useful for exploring other disorders.<\/jats:p>","DOI":"10.3390\/jcm15187040","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T08:17:42Z","timestamp":1789114662000},"page":"7040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating Pharmacodynamic Data to Prioritise Candidate Migraine Genes and Pathways Using a Novel Bioinformatics Workflow"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3834-8212","authenticated-orcid":false,"given":"Mark","family":"Stanworth","sequence":"first","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Altnagelvin Hospital, Londonderry BT47 6SB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Peukert","sequence":"additional","affiliation":[{"name":"Department of Neurology, Royal Victoria Hospital, Belfast HSC Trust, Belfast BT12 6BA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3556-3378","authenticated-orcid":false,"given":"Joanne","family":"Marley","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Ulster University, Belfast BT5 1AP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Puddifoot","sequence":"additional","affiliation":[{"name":"School of Medicine, Ulster University, Londonderry BT48 7JL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9649-0504","authenticated-orcid":false,"given":"Andrew","family":"McDowell","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0170-6809","authenticated-orcid":false,"given":"Elaine","family":"Murray","sequence":"additional","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Altnagelvin Hospital, Londonderry BT47 6SB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7721-0167","authenticated-orcid":false,"given":"Shu-Dong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Personalised Medicine Centre, School of Medicine, Ulster University, C-TRIC Building, Altnagelvin Hospital, Londonderry BT47 6SB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1177\/0333102417716934","article-title":"Musculoskeletal dysfunction in migraine patients","volume":"38","author":"Luedtke","year":"2018","journal-title":"Cephalalgia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41582-022-00763-1","article-title":"Global epidemiology of migraine and its implications for public health and health policy","volume":"19","author":"Steiner","year":"2023","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S0092-8674(00)81373-2","article-title":"Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4","volume":"87","author":"Terwindt","year":"1996","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/ng1081","article-title":"Haploinsufficiency of ATP1A2 encoding the Na+\/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2","volume":"33","author":"Marconi","year":"2003","journal-title":"Nat. Genet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0140-6736(05)66786-4","article-title":"Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine","volume":"366","author":"Dichgans","year":"2005","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019Ayan, A. (2013). Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.1002\/cpz1.90","article-title":"Gene set knowledge discovery with Enrichr","volume":"1","author":"Xie","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"D1265","DOI":"10.1093\/nar\/gkad976","article-title":"DrugBank 6.0: The DrugBank Knowledgebase for 2024","volume":"52","author":"Knox","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"D1003","DOI":"10.1093\/nar\/gkac888","article-title":"Genenames.org: The HGNC resources in 2023","volume":"51","author":"Seal","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"D1467","DOI":"10.1093\/nar\/gkae1128","article-title":"Open Targets Platform: Facilitating therapeutic hypotheses building in drug discovery","volume":"53","author":"Buniello","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pi\u00f1ero, J., Corvi, J., Rykova, N., Guillem, A., Mart\u00ednez, A., Zufiaur, J.T., Rivetta, I., Holmes, S., Del Boccio, M., and Shapoval, D. (2026). DISGENET: Accelerating Data-Driven Discovery in Disease Genomics and Therapeutic Development. bioRxiv.","DOI":"10.64898\/2026.01.05.697749"},{"key":"ref_13","unstructured":"McKusick-Nathans Institute of Genetic Medicine, and Johns Hopkins University (Baltimore, MD) (2026, July 17). Online Mendelian Inheritance in Man, OMIM\u00ae. Available online: https:\/\/omim.org\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1038\/s41588-019-0481-0","article-title":"A global overview of pleiotropy and genetic architecture in complex traits","volume":"51","author":"Watanabe","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"eaao1729","DOI":"10.1126\/science.aao1729","article-title":"Systematic analysis of complex genetic interactions","volume":"360","author":"Kuzmin","year":"2018","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s10194-023-01614-0","article-title":"Debate: Differences and similarities between tension-type headache and migraine","volume":"24","author":"Onan","year":"2023","journal-title":"J. Headache Pain"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mazzaferro, S., Msekela, D.J., Cooper, E.C., Maheshwari, A., and Sine, S.M. (2022). Genetic Variant in Nicotinic Receptor \u03b14-Subunit Causes Sleep-Related Hyperkinetic Epilepsy via Increased Channel Opening. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012124"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e342","DOI":"10.1097\/j.pain.0000000000002360","article-title":"Alcohol, coffee consumption, and smoking in relation to migraine: A bidirectional Mendelian randomization study","volume":"163","author":"Yuan","year":"2022","journal-title":"Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1164\/rccm.201410-1830PP","article-title":"Smoking-induced skeletal muscle dysfunction: From evidence to mechanisms","volume":"191","author":"Degens","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1097\/01.mej.0000209066.13697.15","article-title":"Nicotine gum withdrawal and migraine headaches","volume":"13","author":"Stalnikowicz","year":"2006","journal-title":"Eur. J. Emerg. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1113\/expphysiol.2006.033373","article-title":"Effect of transdermal nicotine administration on exercise endurance in men","volume":"91","author":"Jones","year":"2006","journal-title":"Exp. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/ccr3.886","article-title":"Monocular diplopia-associated migraine-like headache induced by nicotine withdrawal","volume":"5","author":"He","year":"2017","journal-title":"Clin. Case Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/s41467-019-14063-8","article-title":"Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation","volume":"11","author":"Cisterna","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s10974-009-9177-x","article-title":"Altered fast- and slow-twitch muscle fibre characteristics in female mice with a (S248F) knock-in mutation of the brain neuronal nicotinic acetylcholine receptor","volume":"30","author":"Cannata","year":"2009","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_25","first-page":"S7","article-title":"Cervicogenic headache: Mechanisms, evaluation, and treatment strategies","volume":"100","author":"Biondi","year":"2000","journal-title":"J. Am. Osteopath Assoc."},{"key":"ref_26","first-page":"16S","article-title":"Cervicogenic headache: A review of diagnostic and treatment strategies","volume":"105","author":"Biondi","year":"2005","journal-title":"J. Am. Osteopath Assoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1177\/0333102420970184","article-title":"Muscle endurance training of the neck triggers migraine attacks","volume":"41","author":"Carvalho","year":"2021","journal-title":"Cephalalgia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1177\/2049463720924704","article-title":"Involvement of cervical disability in migraine: A literature review","volume":"15","author":"Aoyama","year":"2021","journal-title":"Br. J. Pain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1177\/0333102420919998","article-title":"Increased neck muscle stiffness in migraine patients with ictal neck pain: A shear wave elastography study","volume":"40","author":"Hvedstrup","year":"2020","journal-title":"Cephalalgia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"962651","DOI":"10.1155\/2012\/962651","article-title":"Effects of endurance and resistance training on calcitonin gene-related Peptide and acetylcholine receptor at slow and fast twitch skeletal muscles and sciatic nerve in male wistar rats","volume":"2012","author":"Parnow","year":"2012","journal-title":"Int. J. Pept."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.jbmt.2020.02.025","article-title":"MRI in migraineurs: Are there abnormalities in the area where the myofascial trigger points are palpable and in volume measurements?","volume":"4","author":"Queiroz","year":"2020","journal-title":"J. Bodyw. Mov. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1007\/s004210100409","article-title":"Fibre type proportion and fibre size in trapezius muscle biopsies from cleaners with and without myalgia and its correlation with ragged red fibres, cytochrome-c-oxidase-negative fibres, biomechanical output, perception of fatigue, and surface electromyography during repetitive forward flexions","volume":"84","author":"Larsson","year":"2001","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s10194-022-01503-y","article-title":"What is the efficacy of aerobic exercise versus strength training in the treatment of migraine? A systematic review and network meta-analysis of clinical trials","volume":"23","author":"Woldeamanuel","year":"2022","journal-title":"J. Headache Pain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"C844","DOI":"10.1152\/ajpcell.00402.2005","article-title":"Type II skeletal myofibers possess unique properties that potentiate mitochondrial H(2)O(2) generation","volume":"290","author":"Anderson","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1097\/ALN.0000000000001756","article-title":"Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors","volume":"127","author":"Sugiyama","year":"2017","journal-title":"Anesthesiology"},{"key":"ref_36","first-page":"240","article-title":"Oxidative stress and disuse muscle atrophy: Cause or consequence?","volume":"15","author":"Powers","year":"2012","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/mgg3.346","article-title":"Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes","volume":"6","author":"Luukkonen","year":"2018","journal-title":"Mol. Genet Genom. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jad.2008.11.015","article-title":"Decreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects","volume":"116","author":"Gibbons","year":"2009","journal-title":"J. Affect Disord."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1016\/j.celrep.2018.07.082","article-title":"Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM Sleep","volume":"24","author":"Niwa","year":"2018","journal-title":"Cell Rep."},{"key":"ref_40","first-page":"820","article-title":"Serum calcium and risk of migraine: A Mendelian randomization study","volume":"26","author":"Yin","year":"2017","journal-title":"Hum. Mol. Genet"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Turi, Z., Hananeia, N., Shirinpour, S., Opitz, A., Jedlicka, P., and Vlachos, A. (2022). Dosing Transcranial Magnetic Stimulation of the Primary Motor and Dorsolateral Prefrontal Cortices With Multi-Scale Modeling. Front Neurosci., 16.","DOI":"10.3389\/fnins.2022.929814"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1007\/s10571-016-0340-9","article-title":"SCN2B in the Rat Trigeminal Ganglion and Trigeminal Sensory Nuclei","volume":"36","author":"Shimada","year":"2016","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"104598","DOI":"10.1016\/j.jpain.2024.104598","article-title":"MicroRNA-6954-3p Downregulation Contributes to Orofacial Neuropathic Pain in Mice Via Targeting Voltage-Gated Sodium Channel \u03b22 Subunit Protein","volume":"25","author":"Liu","year":"2024","journal-title":"J. Pain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1136\/bmj.2.4745.1424","article-title":"An investigation of the salt and water balance in migraine","volume":"2","author":"Campbell","year":"1951","journal-title":"Br. Med. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s10072-019-04113-w","article-title":"Identification of common genetic markers of paroxysmal neurological disorders using a network analysis approach","volume":"41","author":"Ilyas","year":"2020","journal-title":"Neurol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1111\/ene.14098","article-title":"Poor patient awareness and frequent misdiagnosis of migraine: Findings from a large transcontinental cohort","volume":"27","author":"Viana","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Albury, C.L., Sutherland, H.G., Lam, A.W.Y., Tran, N.K., Lea, R.A., Haupt, L.M., and Griffiths, L.R. (2024). Identification of Polymorphisms in EAAT1 Glutamate Transporter Gene SLC1A3 Associated with Reduced Migraine Risk. Genes, 15.","DOI":"10.3390\/genes15060797"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/18\/7040\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T08:48:00Z","timestamp":1789116480000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/18\/7040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":47,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jcm15187040"],"URL":"https:\/\/doi.org\/10.3390\/jcm15187040","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]}}}