A genetic interaction of NRXN2 with GABRE, SYT1 and CASK in migraine patients: a case-control study

• Published in: Journal of headache and pain 2021-06, Vol.22 (1), p.57-57, Article 57
• Main Authors: Alves-Ferreira, Miguel, Quintas, Marlene, Sequeiros, Jorge, Sousa, Alda, Pereira-Monteiro, José, Alonso, Isabel, Neto, João Luís, Lemos, Carolina
• Format: Article
• Language: English
• Subjects: Case-Control Studies; Female; Females; Gender differences; Gene Frequency; Gene-gene interaction; Genetic Predisposition to Disease; Genetic variants; Genotype; Genotype & phenotype; Guanylate Kinases - genetics; Haplotypes; Headache; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Migraine; Migraine Disorders - genetics; Nerve Tissue Proteins - genetics; Neurexin; Neurology; Neurotransmission; Neurotransmitter; Neurotransmitter release; Pain Medicine; Polymorphism, Single Nucleotide; Receptors, GABA-A - genetics; Research Article; Single-nucleotide polymorphism; Statistical analysis; Susceptibility; Synaptic vesicles; Synaptotagmin I - genetics; Vesicle fusion; Womens health; γ-Aminobutyric acid A receptors
• ISSN: 1129-2369; 1129-2377
• DOI: 10.1186/s10194-021-01266-y

Background Migraine is a multifactorial disorder that is more frequent (two to four times) in women than in men. In recent years, our research group has focused on the role of neurotransmitter release and its regulation. Neurexin ( NRXN2 ) is one of the components of the synaptic vesicle machinery, responsible for connecting intracellular fusion proteins and synaptic vesicles. Our aim was to continue exploring the role and interaction of proteins involved in the control and promotion of neurotransmission in migraine susceptibility. Methods 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 NRXN2 were genotyped to assess the association between NRXN2 and migraine susceptibility. The χ 2 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. Results We found a statistically significant interaction model ( p  = 0.009) in the female group between the genotypes CG of rs477138 ( NRXN2 ) and CT of rs1158605 ( GABRE ). This interaction was validated by logistic regression, showing a significant risk effect [OR = 4.78 (95%CI: 1.76–12.97)] after a Bonferroni correction. Our data also supports a statistically significant interaction model ( p  = 0.011) in the female group between the GG of rs477138 in NRXN2 and, the rs2244325's GG genotype and rs2998250’s CC genotype of CASK . This interaction was also validated by logistic regression, with a protective effect [OR = 0.08 (95%CI: 0.01–0.75)]. A weak interaction model was found between NRXN2 - SYT1 . We have not found any statistically significant allelic or haplotypic associations between NRXN2 and migraine susceptibility. Conclusions This study unravels, for the first time, the gene-gene interactions between NRXN2 , GABRE - a GABA A -receptor - and CASK , importantly it shows the synergetic effect between those genes and its relation with migraine susceptibility. 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.