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In recent years, our research group has focused on the role of neurotransmitter release and its regulation. Neurexin (<jats:italic>NRXN2<\/jats:italic>) is one of the components of the synaptic vesicle machinery, responsible for connecting intracellular fusion proteins and synaptic vesicles.<\/jats:p>\n                <jats:p>Our aim was to continue exploring the role and interaction of proteins involved in the control and promotion of neurotransmission in migraine susceptibility.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A case-control study was performed comprising 183 migraineurs (148 females and 35 males) and 265 migraine-free controls (202 females and 63 males). Tagging single nucleotide polymorphisms of <jats:italic>NRXN2<\/jats:italic> were genotyped to assess the association between <jats:italic>NRXN2<\/jats:italic> and migraine susceptibility. The \u03c7<jats:sup>2<\/jats:sup> test was used to compare allele frequencies in cases and controls and odds ratios were estimated with 95% confidence intervals. Haplotype frequencies were compared between groups. Gene-gene interactions were analysed using the Multifactor Dimensionality Reduction v2.0.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found a statistically significant interaction model (<jats:italic>p<\/jats:italic>\u00a0=\u20090.009) in the female group between the genotypes CG of rs477138 (<jats:italic>NRXN2<\/jats:italic>) and CT of rs1158605 (<jats:italic>GABRE<\/jats:italic>). This interaction was validated by logistic regression, showing a significant risk effect [OR\u2009=\u20094.78 (95%CI: 1.76\u201312.97)] after a Bonferroni correction. Our data also supports a statistically significant interaction model (<jats:italic>p<\/jats:italic>\u00a0=\u20090.011) in the female group between the GG of rs477138 in <jats:italic>NRXN2<\/jats:italic> and, the rs2244325's GG genotype and rs2998250\u2019s CC genotype of <jats:italic>CASK<\/jats:italic>. This interaction was also validated by logistic regression, with a protective effect [OR\u2009=\u20090.08 (95%CI: 0.01\u20130.75)]. A weak interaction model was found between <jats:italic>NRXN2<\/jats:italic>-<jats:italic>SYT1<\/jats:italic>. We have not found any statistically significant allelic or haplotypic associations between <jats:italic>NRXN2<\/jats:italic> and migraine susceptibility.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study unravels, for the first time, the gene-gene interactions between <jats:italic>NRXN2<\/jats:italic>, <jats:italic>GABRE -<\/jats:italic> a GABA<jats:sub>A<\/jats:sub>-receptor - and <jats:italic>CASK<\/jats:italic>, importantly it shows the synergetic effect between those genes and its relation with migraine susceptibility.<\/jats:p>\n                <jats:p>These gene interactions, which may be a part of a larger network, can potentially help us in better understanding migraine aetiology and in development of new therapeutic approaches.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s10194-021-01266-y","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T08:16:49Z","timestamp":1623658609000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A genetic interaction of NRXN2 with GABRE, SYT1 and CASK in migraine patients: a case-control study"],"prefix":"10.1186","volume":"22","author":[{"given":"Miguel","family":"Alves-Ferreira","sequence":"first","affiliation":[]},{"given":"Marlene","family":"Quintas","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"Sequeiros","sequence":"additional","affiliation":[]},{"given":"Alda","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9","family":"Pereira-Monteiro","sequence":"additional","affiliation":[]},{"given":"Isabel","family":"Alonso","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o Lu\u00eds","family":"Neto","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-9584","authenticated-orcid":false,"given":"Carolina","family":"Lemos","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"issue":"10100","key":"1266_CR1","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1016\/S0140-6736(17)32154-2","volume":"390","author":"GBD Disease","year":"2017","unstructured":"Disease GBD, Injury I, Prevalence C (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. 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