{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:51:55Z","timestamp":1786517515635,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 114-2320-B-039-017"],"award-info":[{"award-number":["NSTC 114-2320-B-039-017"]}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-112-155"],"award-info":[{"award-number":["DMR-112-155"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-114-042"],"award-info":[{"award-number":["DMR-114-042"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-114-189"],"award-info":[{"award-number":["DMR-114-189"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-115-001"],"award-info":[{"award-number":["DMR-115-001"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Migraine is a complex neurovascular disorder in which immune signaling intersects with vascular and neural circuits, yet the tissue and cell-type context of common genetic risk remains incompletely defined. We integrated large-scale migraine genome-wide association study (GWAS) summary statistics with Genotype-Tissue Expression (GTEx) v8 expression and splicing quantitative trait loci (eQTLs and sQTLs), Bayesian co-localization, single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from migraine cases and controls, a healthy single-cell multi-omics atlas (assay for transposase-accessible chromatin (ATAC) plus RNA), high-dimensional weighted gene co-expression network analysis (hdWGCNA), and embryo-level spatial transcriptomics. Genetic signals were enriched in peripheral arteries, heart, and blood, and gene-level enrichment highlighted mucosal\u2013smooth muscle organs including the bladder and the cervix endocervix. Cell-type prioritization consistently implicated endothelial and vascular smooth muscle lineages, with additional support for inhibitory interneurons and bladder epithelium. In PBMC T cells, co-expression modules capturing cytotoxic\/activation and T-cell receptor signaling programs contained migraine-prioritized genes, including PTK2B, nominating immune activation circuitry as a component of genetic susceptibility. Spatial projection further localized risk concordance to craniofacial\/meningeal interfaces and visceral smooth muscle\u2013mucosal structures. Together, these analyses delineate a systemic neuroimmune\u2013vascular architecture for migraine and provide genetically anchored candidate pathways and targets for mechanistic and therapeutic follow-up.<\/jats:p>","DOI":"10.3390\/ijms27031615","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T16:32:59Z","timestamp":1770395579000},"page":"1615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unraveling the Cross-Tissue Neuroimmune\u2013Vascular Genetic Architecture of Migraine Using Integrated Multi-Omics, Single-Cell, and Spatial Transcriptomics: Prioritizing T-Cell Regulatory Networks and Peripheral Targets"],"prefix":"10.3390","volume":"27","author":[{"given":"Chung-Chih","family":"Liao","sequence":"first","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Integrated Chinese and Western Medicine, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke-Ru","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yuanlin Christian Hospital, Yuanlin 51052, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7069-8510","authenticated-orcid":false,"given":"Jung-Miao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s10194-020-01208-0","article-title":"Migraine remains second among the world\u2019s causes of disability, and first among young women: Findings from GBD2019","volume":"21","author":"Steiner","year":"2020","journal-title":"J. Headache Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102348","DOI":"10.1016\/j.xcrm.2025.102348","article-title":"Global, regional, and national burden of headache disorders, 1990-2021, with forecasts to 2050: A Global Burden of Disease study 2021","volume":"6","author":"Wijeratne","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lu, Y., Li, Q.-y., Gan, L., You, Y., Wang, C.-d., Guo, Z.-w., Shi, J., and Liu, X.-y. (2025). The global and regional burden and trends of migraine from 1990 to 2021: Global Burden of Disease Study 2021. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1686288"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s40122-024-00690-7","article-title":"The Global Burden of Migraine: A 30-Year Trend Review and Future Projections by Age, Sex, Country, and Region","volume":"14","author":"Dong","year":"2025","journal-title":"Pain Ther."},{"key":"ref_5","first-page":"1334","article-title":"Burden of Illness Among People with Migraine and \u22654 Monthly Headache Days While Using Acute and\/or Preventive Prescription Medications for Migraine","volume":"26","author":"Buse","year":"2020","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1111\/j.1526-4610.2009.01369.x","article-title":"Economic burden of transformed migraine: Results from the American Migraine Prevalence and Prevention (AMPP) Study","volume":"49","author":"Munakata","year":"2009","journal-title":"Headache"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Frimpong-Manson, K., Ortiz, Y.T., McMahon, L.R., and Wilkerson, J.L. (2024). Advances in understanding migraine pathophysiology: A bench to bedside review of research insights and therapeutics. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1355281"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1056\/NEJMra1915327","article-title":"Migraine","volume":"383","author":"Ashina","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1152\/physrev.00034.2015","article-title":"Pathophysiology of Migraine: A Disorder of Sensory Processing","volume":"97","author":"Goadsby","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1093\/brain\/aww097","article-title":"The migraine generator revisited: Continuous scanning of the migraine cycle over 30 days and three spontaneous attacks","volume":"139","author":"Schulte","year":"2016","journal-title":"Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6619","DOI":"10.1523\/JNEUROSCI.0373-15.2015","article-title":"Migraine: Multiple processes, complex pathophysiology","volume":"35","author":"Burstein","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/S1474-4422(16)30293-9","article-title":"Sex differences in the epidemiology, clinical features, and pathophysiology of migraine","volume":"16","author":"Vetvik","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Karsan, N., and Goadsby, P.J. (2021). Migraine Is More Than Just Headache: Is the Link to Chronic Fatigue and Mood Disorders Simply Due to Shared Biological Systems?. Front. Hum. Neurosci., 15.","DOI":"10.3389\/fnhum.2021.646692"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41588-021-00990-0","article-title":"Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles","volume":"54","author":"Hautakangas","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hautakangas, H., Palotie, A., Pirinen, M., FinnGen, International Headache Genetics Consortium, and HUNT All-in Headache (2024). Fine-mapping a genome-wide meta-analysis of 98,374 migraine cases identifies 181 sets of candidate causal variants. medRxiv.","DOI":"10.1101\/2024.05.20.24307608"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41572-021-00328-4","article-title":"Migraine","volume":"8","author":"Ferrari","year":"2022","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s10194-021-01271-1","article-title":"Migraine and neuroinflammation: The inflammasome perspective","volume":"22","author":"Kursun","year":"2021","journal-title":"J. Headache Pain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s10194-024-01800-8","article-title":"Altered immunity in migraine: A comprehensive scoping review","volume":"25","author":"Ha","year":"2024","journal-title":"J. Headache Pain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.37796\/2211-8039.1174","article-title":"Inflammation, oxidative stress, insulin resistance, and hypertension as mediators for adverse effects of obesity on the brain: A review","volume":"11","author":"Ghowsi","year":"2021","journal-title":"Biomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s10194-025-02075-3","article-title":"The lactylation\u2013immune regulatory axis: A potential therapeutic target for migraine prevention and treatment","volume":"26","author":"Wang","year":"2025","journal-title":"J. Headache Pain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/head.14832","article-title":"Heightened migraine risk in patients with rheumatoid arthritis: A national retrospective cohort study","volume":"65","author":"Kang","year":"2025","journal-title":"Headache"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"105946","DOI":"10.1016\/j.nbd.2022.105946","article-title":"Role of PACAP in migraine: An alternative to CGRP?","volume":"176","author":"Guo","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00415-025-13177-y","article-title":"Concomitant anti-CGRP and immunomodulatory treatments in patients with migraine: Towards integrated management strategies","volume":"272","author":"Caronna","year":"2025","journal-title":"J. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1186\/s10194-025-02179-w","article-title":"A single-cell multi-omics framework identifies immune cell drivers of migraine and repurposable therapeutics","volume":"26","author":"Li","year":"2025","journal-title":"J. Headache Pain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13030-023-00275-4","article-title":"Systematic review and meta-analysis of calculating degree of comorbidity of irritable bowel syndrome with migraine","volume":"17","author":"Todor","year":"2023","journal-title":"Biopsychosoc. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s10194-020-1078-9","article-title":"School of Advanced Studies of the European Headache Federation. Gut-brain Axis and migraine headache: A comprehensive review","volume":"21","author":"Arzani","year":"2020","journal-title":"J. Headache Pain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8149","DOI":"10.3748\/wjg.v22.i36.8149","article-title":"Gastrointestinal disorders associated with migraine: A comprehensive review","volume":"22","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s10194-016-0645-6","article-title":"Autonomous control of cardiovascular reactivity in patients with episodic and chronic forms of migraine","volume":"17","author":"Mamontov","year":"2016","journal-title":"J. Headache Pain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(19)30185-1","article-title":"Migraine and the trigeminovascular system-40 years and counting","volume":"18","author":"Ashina","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tanaka, M., Szab\u00f3, \u00c1., K\u00f6rt\u00e9si, T., Szok, D., Tajti, J., and V\u00e9csei, L. (2023). From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment. Cells, 12.","DOI":"10.20944\/preprints202309.0459.v2"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3738","DOI":"10.1111\/ejn.15676","article-title":"Current perspectives on mitochondrial dysfunction in migraine","volume":"56","author":"Bohra","year":"2022","journal-title":"Eur. J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Li, H., Fu, Q., Philips, K., Sun, Y., Faurot, K.R., Gaylord, S.A., and Mann, J.D. (2022). Leukocyte inflammatory phenotype and function in migraine patients compared with matched non-migraine volunteers: A pilot study. BMC Neurol., 22.","DOI":"10.1186\/s12883-022-02781-4"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1097\/WCO.0b013e32833821c1","article-title":"An update on the blood vessel in migraine","volume":"23","author":"Brennan","year":"2010","journal-title":"Curr. Opin. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kugler, E.C., Greenwood, J., and MacDonald, R.B. (2021). The \"Neuro-Glial-Vascular\" Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.732820"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1111\/j.1468-2982.2007.01500.x","article-title":"Is the cerebral cortex hyperexcitable or hyperresponsive in migraine?","volume":"27","author":"Coppola","year":"2007","journal-title":"Cephalalgia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e142202","DOI":"10.1172\/JCI142202","article-title":"Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model","volume":"131","author":"Auffenberg","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Li, G., Duan, S., Zheng, T., Zhu, T., Qu, B., Liu, L., and Liu, Z. (2024). Genetic causal relationship between immune diseases and migraine: A Mendelian randomization study. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1376698"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"de Pins, B., Mendes, T., Giralt, A., and Girault, J.A. (2021). The Non-receptor Tyrosine Kinase Pyk2 in Brain Function and Neurological and Psychiatric Diseases. Front. Synaptic Neurosci., 13.","DOI":"10.3389\/fnsyn.2021.749001"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lee, D., and Hong, J.H. (2022). Activated PyK2 and Its Associated Molecules Transduce Cellular Signaling from the Cancerous Milieu for Cancer Metastasis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415475"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1111\/j.1538-7836.2005.01371.x","article-title":"Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability","volume":"3","author":"Lillis","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.jare.2025.03.005","article-title":"The LRP1-SHP2 pathway regulates TRPV1 sensitivity in the peripheral nervous system: Insights from amyloid beta 1-42 modulation","volume":"79","author":"Hwang","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/35004606","article-title":"Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta","volume":"404","author":"Schlossmann","year":"2000","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12551","DOI":"10.1074\/jbc.M313365200","article-title":"InsP3R-associated cGMP kinase substrate (IRAG) is essential for nitric oxide-induced inhibition of calcium signaling in human colonic smooth muscle","volume":"279","author":"Fritsch","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pr\u00fcschenk, S., Majer, M., and Schlossmann, J. (2023). Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202305.1221.v1"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s10194-024-01828-w","article-title":"Multi-omics Mendelian randomization integrating GWAS, eQTL and pQTL data revealed GSTM4 as a potential drug target for migraine","volume":"25","author":"Sun","year":"2024","journal-title":"J. Headache Pain"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s10194-025-01950-3","article-title":"Machine learning-driven identification of critical gene programs and key transcription factors in migraine","volume":"26","author":"Zhang","year":"2025","journal-title":"J. Headache Pain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1177\/03331024211068065","article-title":"NCOR2 is a novel candidate gene for migraine-epilepsy phenotype","volume":"42","author":"Nuottamo","year":"2022","journal-title":"Cephalalgia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1111\/imm.13863","article-title":"Multiomic-based immune response profiling in migraine, vestibular migraine and Meniere\u2019s disease","volume":"173","author":"Frejo","year":"2024","journal-title":"Immunology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"eadp4753","DOI":"10.1126\/science.adp4753","article-title":"Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants","volume":"387","author":"Liu","year":"2025","journal-title":"Science"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1615\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T05:15:04Z","timestamp":1770527704000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,6]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27031615"],"URL":"https:\/\/doi.org\/10.3390\/ijms27031615","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,6]]}}}