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

Miguel Alves-Ferreira,Jorge Sequeiros,Carolina Lemos,Marlene Quintas,Alda Sousa,José Pereira-Monteiro,João Luís Neto,Isabel Alonso

doi:10.1186/s10194-021-01266-y

Abstract

BackgroundMigraine 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.MethodsA 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 χ2 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.ResultsWe 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.ConclusionsThis study unravels, for the first time, the gene-gene interactions between NRXN2, GABRE - a GABAA-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.

Highlights

Migraine is a multifactorial disorder that is more frequent in women than in men
This study unravels, for the first time, the gene-gene interactions between NRXN2, Gamma-aminobutyric acid type A receptor epsilon subunit (GABRE) - a GABAAreceptor - and calmodulin-dependent serine protein kinase (CASK), importantly it shows the synergetic effect between those genes and its relation with migraine susceptibility
We have focused on the synaptic vesicles’ machinery and life-cycle, as our group identified in the Portuguese population two risk variants in the STX1A gene [10] coding for syntaxin 1A, a constituent of the SNAP REceptor (SNARE) complex, with a fundamental role in neurotransmission control

Summary

Introduction

Migraine is a multifactorial disorder that is more frequent (two to four times) in women than in men. Migraine is a multifactorial disease that results from the small contributions of several genetic and environmental factors and affects more women than men (two to four times) [3]. An increased familial risk for migraine was found in several studies, including in Portuguese families, indicating that migraine has a genetic component [4, 5]. 47 genetic susceptibility loci associated with migraine have been reported by genome-wide association studies (GWAS) [6]. Candidate gene association studies, including in our population, have focused on pathways related to migraine triggers and pathophysiology, namely in genes involved in the vascular and hormonal component and in the release of neurotransmitters [8, 9]

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