{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:02:53Z","timestamp":1785402173035,"version":"3.56.0"},"reference-count":52,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sociedade Portuguesa de Cefaleias"},{"id":[{"id":"https:\/\/ror.org\/015w8p155","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Novartis"},{"name":"FCT","award":["POCI-01-0145-FEDER-029486 (PTDC\/MEC-NEU\/29486\/2017)"],"award-info":[{"award-number":["POCI-01-0145-FEDER-029486 (PTDC\/MEC-NEU\/29486\/2017)"]}]},{"award":["POCI-01-0145-FEDER-029486 (PTDC\/MEC-NEU\/29486\/2017)"],"award-info":[{"award-number":["POCI-01-0145-FEDER-029486 (PTDC\/MEC-NEU\/29486\/2017)"]}],"id":[{"id":"https:\/\/ror.org\/00snfqn58","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Common forms of migraine are complex disorders characterized by significant clinical diversity. Their genetic basis has been extensively studied but remains unclear. This study represents the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility loci through a case\u2013control study and unravel population-specific variants. Genotyping data was acquired with Applied Biosystems Axiom\u2122 PMDA array, producing 12,035,248 single-nucleotide polymorphisms (SNPs) post-imputation, providing a comprehensive scope for GWAS analysis. PRS models were created and tested using a k-folds cross-validation framework and the optimal significance threshold was assessed. We detected 12 potential risk loci corresponding to 12 lead SNPs (RP11-204N11.2, CTA-481E9.4\/CTA-481E9.3, RAP1A, TIGD4, CADPS2, RP11-46E17.6, RP4-569D19.5, RP11-398K14.1, PCBP1-AS1, TCF15, IL6R and UNC13A). The top three variants (RP11-204N11.2, CTA-481E9.4\/CTA-481E9.3 and RAP1A) were also supported by the PRS model. We highlight that several variants present putative biological relevance to migraine pathophysiology, reinforcing the importance of neurotransmitter release, synaptic transmission and the involvement of vascular components in migraine pathophysiology.<\/jats:p>","DOI":"10.3390\/ijms27125165","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:43:46Z","timestamp":1780897426000},"page":"5165","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Potential Risk Loci for Migraine in the Portuguese Population"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1730-522X","authenticated-orcid":false,"given":"Rodrigo","family":"De Marco","sequence":"first","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Rua das Taipas 135, 4050-600 Porto, Portugal"},{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Pucci","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2343-2215","authenticated-orcid":false,"given":"Mariana","family":"Santos","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Gil-Gouveia","sequence":"additional","affiliation":[{"name":"Hospital da Luz Headache Center, Neurology Department, Hospital da Luz Lisboa, Avenida Lus\u00edada 100, 1500-650 Lisbon, Portugal"},{"name":"Center for Interdisciplinary Research in Health, Universidade Cat\u00f3lica Portuguesa, Palma de Cima, 1649-023 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Cavadas","sequence":"additional","affiliation":[{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alda","family":"Sousa","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4275-9598","authenticated-orcid":false,"given":"Miguel","family":"Alves-Ferreira","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"CGPP-Centro de Gen\u00e9tica Preditiva e Preventiva, i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u00edsa","family":"Azevedo","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Rua das Taipas 135, 4050-600 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Lemos","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Rua das Taipas 135, 4050-600 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1070-9606","authenticated-orcid":false,"given":"Andreia","family":"Dias","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Rua das Taipas 135, 4050-600 Porto, Portugal"},{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1001\/archinte.1928.00130210138013","article-title":"The inheritance of migraine","volume":"42","author":"Allan","year":"1928","journal-title":"Arch. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e70007","DOI":"10.1111\/ejn.70007","article-title":"Neural Plasticity in Migraine Chronification","volume":"61","author":"Fila","year":"2025","journal-title":"Eur. J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00439-021-02389-7","article-title":"A review of migraine genetics: Gathering genomic and transcriptomic factors","volume":"141","author":"Dias","year":"2022","journal-title":"Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1517\/13543784.10.4.673","article-title":"Substance P receptor antagonists in the therapy of migraine","volume":"10","author":"May","year":"2001","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1007\/s00415-023-11706-1","article-title":"Migraine: From pathophysiology to treatment","volume":"270","author":"Puledda","year":"2023","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s10194-018-0956-x","article-title":"Novel hypotheses emerging from GWAS in migraine?","volume":"20","author":"Nyholt","year":"2019","journal-title":"J. Headache Pain"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.cell.2019.02.048","article-title":"The Missing Diversity in Human Genetic Studies","volume":"177","author":"Sirugo","year":"2019","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dudbridge, F. (2013). Power and Predictive Accuracy of Polygenic Risk Scores. PLoS Genet., 9, Erratum in PLoS Genet.\u00a02013, 9. https:\/\/doi.org\/10.1371\/annotation\/b91ba224-10be-409d-93f4-7423d502cba0.","DOI":"10.1371\/annotation\/b91ba224-10be-409d-93f4-7423d502cba0"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s10194-023-01547-8","article-title":"Genetics of migraine: Where are we now?","volume":"24","author":"Grangeon","year":"2023","journal-title":"J. Headache Pain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e364","DOI":"10.1212\/NXG.0000000000000364","article-title":"Migraine polygenic risk score associates with efficacy of migraine-specific drugs","volume":"5","author":"Kogelman","year":"2019","journal-title":"Neurol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e70316","DOI":"10.1111\/ene.70316","article-title":"The Spectrum of Headaches in Moyamoya Angiopathy: From Mechanisms to Management Strategies\u2014A Consensus Review From the NEUROVASC Working Group","volume":"32","author":"Rifino","year":"2025","journal-title":"Eur. J. Neurol."},{"key":"ref_14","unstructured":"(2026, April 30). GWAS Catalog. Variant: rs7525578. Available online: https:\/\/www.ebi.ac.uk\/gwas\/variants\/rs7525578."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1046\/j.1468-2982.1996.1604231.x","article-title":"Work-related disability: Results from the American migraine study","volume":"16","author":"Stewart","year":"1996","journal-title":"Cephalalgia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.neuron.2018.03.049","article-title":"Ras and Rap Signal Bidirectional Synaptic Plasticity via Distinct Subcellular Microdomains","volume":"98","author":"Zhang","year":"2018","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cherra, S.J., and Lamb, R. (2024). Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1352731"},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1177\/1073858410365562","article-title":"Ras and Rap signaling in synaptic plasticity and mental disorders","volume":"17","author":"Stornetta","year":"2011","journal-title":"Neuroscientist"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6538","DOI":"10.1074\/jbc.M109.069948","article-title":"G protein \u03b2\u03b3 subunits regulate cell adhesion through Rap1a and its effector Radil","volume":"285","author":"Ahmed","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/s10038-023-01167-9","article-title":"Genome-wide association study identifies novel susceptibilities to adult moyamoya disease","volume":"68","author":"Jeon","year":"2023","journal-title":"J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"euaf042","DOI":"10.1093\/europace\/euaf042","article-title":"Identification of a new genetic locus associated with atrial fibrillation in the Taiwanese population by genome-wide and transcriptome-wide association studies","volume":"27","author":"Lee","year":"2025","journal-title":"Europace"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mohammad, S., Bussu, G., Rukh, G., Schi\u00f6th, H.B., and Mwinyi, J. (2025). Migraine and its major subtypes\u2014With and without aura are associated with polygenic scores for autism. Cephalalgia, 45.","DOI":"10.1177\/03331024241312666"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1093\/brain\/awab267","article-title":"Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools","volume":"145","author":"Bahrami","year":"2022","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1177\/0333102415621055","article-title":"The migraine-stroke connection: A genetic perspective","volume":"36","author":"Malik","year":"2016","journal-title":"Cephalalgia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1523\/JNEUROSCI.2528-03.2004","article-title":"The Secretory Granule-Associated Protein CAPS2 Regulates Neurotrophin Release and Cell Survival","volume":"24","author":"Sadakata","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1523\/JNEUROSCI.2279-06.2007","article-title":"Impaired cerebellar development and function in mice lacking CAPS2, a protein involved in neurotrophin release","volume":"27","author":"Sadakata","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1172\/JCI29031","article-title":"Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients","volume":"117","author":"Sadakata","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/emmm.201303235","article-title":"Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients","volume":"6","author":"Bonora","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.bbrc.2017.06.134","article-title":"CADPS2 gene expression is oppositely regulated by LRRK2 and alpha-synuclein","volume":"490","author":"Obergasteiger","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9037","DOI":"10.1073\/pnas.122623799","article-title":"Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming","volume":"99","author":"Varoqueaux","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1001\/archneurol.2010.37","article-title":"Evidence of syntaxin 1A involvement in migraine susceptibility: A Portuguese study","volume":"67","author":"Lemos","year":"2010","journal-title":"Arch. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s10194-023-01615-z","article-title":"Non-coding variants in VAMP2 and SNAP25 affect gene expression: Potential implications in migraine susceptibility","volume":"24","author":"Dias","year":"2023","journal-title":"J. Headache Pain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/ng.3622","article-title":"Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis","volume":"48","author":"Shatunov","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"630.e3","DOI":"10.1016\/j.neurobiolaging.2011.10.029","article-title":"UNC13A is a modifier of survival in amyotrophic lateral sclerosis","volume":"33","author":"Diekstra","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41586-022-04436-3","article-title":"TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A","volume":"603","author":"Brown","year":"2022","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41586-022-04424-7","article-title":"TDP-43 represses cryptic exon inclusion in the FTD\u2013ALS gene UNC13A","volume":"603","author":"Ma","year":"2022","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1136\/jnnp-2022-330504","article-title":"UNC13A in amyotrophic lateral sclerosis: From genetic association to therapeutic target","volume":"94","author":"Willemse","year":"2023","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101315","DOI":"10.1016\/j.gendis.2024.101315","article-title":"De novo missense variants of UNC13A are implicated in epileptic encephalopathies and neurodevelopmental disorders","volume":"12","author":"Su","year":"2025","journal-title":"Genes Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1212\/NXG.0000000000000105","article-title":"Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia","volume":"2","author":"Engel","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.neurol.2021.07.008","article-title":"Cortical excitability in migraine: Contributions of magnetic resonance imaging","volume":"177","author":"Gollion","year":"2021","journal-title":"Rev. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1177\/13524585251371984","article-title":"Genomewide association study of a homogeneous multiple sclerosis cohort: Tumefactive demyelination","volume":"31","author":"Decker","year":"2025","journal-title":"Mult. Scler. J."},{"key":"ref_43","first-page":"438","article-title":"LncRNA PCBP1-AS1 Induces Cerebral Ischemia\/Reperfusion Injury via the miR-506-3p\/CCL2 Axis","volume":"53","author":"He","year":"2023","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_44","first-page":"5281","article-title":"Sub-pathway analysis for severe burns injury patients: Identification of potential key lncRNAs by analyzing lncRNA-mRNA profile","volume":"15","author":"Tang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wen, S., Yu, C., Kelsey, M.M.G., Pereira, M., Alaimo, H., Teixeira, E., Pracht, J., Daiello, L.A., Drake, J., and Sedivy, J.M. (2026). RNA transcripts in salivary extracellular vesicle cargo isolated from aged populations. Front. Aging, 6.","DOI":"10.3389\/fragi.2025.1707720"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"42959","DOI":"10.1074\/jbc.M111.295758","article-title":"Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor","volume":"286","author":"Garbers","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101044","DOI":"10.1016\/j.bbih.2025.101044","article-title":"Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer\u2019s disease","volume":"47","author":"Siciliano","year":"2025","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"103826","DOI":"10.1016\/j.autrev.2025.103826","article-title":"Interleukin-6 in neuroimmunological disorders: Pathophysiology and therapeutic advances with satralizumab","volume":"24","author":"Li","year":"2025","journal-title":"Autoimmun. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/gepi.20398","article-title":"Quantifying and correcting for the winner\u2019s curse in genetic association studies","volume":"33","author":"Xiao","year":"2009","journal-title":"Genet. Epidemiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.1038\/s41596-020-0353-1","article-title":"Tutorial: A guide to performing polygenic risk score analyses","volume":"15","author":"Choi","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Dickson, S.P., Wang, K., Krantz, I., Hakonarson, H., and Goldstein, D.B. (2010). Rare Variants Create Synthetic Genome-Wide Associations. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000294"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Headache Classification Committee of the International Headache Society (IHS) (2018). The International Classification of Headache Disorders, 3rd edition. Cephalalgia, 38, 1\u2013211.","DOI":"10.1177\/0333102417738202"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5165\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T04:15:18Z","timestamp":1780978518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,6]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125165"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125165","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,6]]}}}