Abstract
Migraine is a common neurological episodic disorder with a female-to-male prevalence 3- to 4-fold higher, suggesting a possible X-linked genetic component. Our aims were to assess the role of common variants of gamma-aminobutyric acid A receptor (GABAAR) genes, located in the X-chromosome, in migraine susceptibility and the possible interaction between them. An association study with 188 unrelated cases and 286 migraine-free controls age- and ethnic matched was performed. Twenty-three tagging SNPs were selected in three genes (GABRE, GABRA3 and GABRQ). Allelic, genotypic and haplotypic frequencies were compared between cases and controls. We also focused on gene-gene interactions. The AT genotype of rs3810651 of GABRQ gene was associated with an increased risk for migraine (OR: 4.07; 95% CI: 1.71-9.73, p=0.002), while the CT genotype of rs3902802 (OR: 0.41; 95% CI: 0.21-0.78, p=0.006) and GA genotype of rs2131190 of GABRA3 gene (OR: 0.53; 95% CI: 0.32-0.88, p=0.013) seem to be protective factors. All associations were found in the female group and maintained significance after Bonferroni correction. We also found three nominal associations in the allelic analyses although there were no significant results in the haplotypic analyses. Strikingly, we found strong interactions between six SNPs encoding for different subunits of GABAAR, all significant after permutation correction. To our knowledge, we show for the first time, the putative involvement of polymorphisms in GABAAR genes in migraine susceptibility and more importantly we unraveled a role for novel gene-gene interactions opening new perspectives for the development of more effective treatments.
Highlights
Migraine is a common and often debilitating neurological disorder
Taking into account that gammaaminobutyric acid A receptor (GABAAR) genes are located in the X-chromosome our analysis was stratified by gender and genotypic analyses were only performed in the female group
While many unanswered questions remain around migraine pathophysiology, some evidence point to the involvement of Gamma-aminobutyric acid (GABA) and it receptors in this process [38]
Summary
Migraine is a common and often debilitating neurological disorder. The knowledge of its underlying pathophysiology is still limited, it is considered as a peculiar response of the central nervous system (CNS) to a variety of environmental and genetic components [1,2]. Mutations or polymorphisms in genes involved in ion channel and neurotransmitter pathways, vascular functions and hormonal mechanisms are considered key factors for migraine susceptibility [3]. Experimental pharmacology and human genetic data support a model for migraine based on a neuronal hyperexcitability and activation of the trigeminovascular system [4,5]. We have shown in the Portuguese population that gender is a critical risk factor for migraine and a gender-biased transmission is observed [9]. This can be explained by a migraine susceptibility locus on the X-chromosome [10], Xq24-28, which was identified in an Australian study in two large families [11]
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