Identification of a novel ANKK1 and other dopaminergic (DRD2 and DBH) gene variants in migraine susceptibility

Abstract

The dopaminergic system plays an important role in migraine and its clinical subtypes. Hypersensitization of dopamine receptor type 2 (DRD2) in migraine led to successful administration of receptor antagonists in antimigraine therapy. Ankyrin repeats and kinase domain containing 1 (ANKK1) gene in DRD2 loci is linked to comorbid neurological disorders. Dopamine beta hydroxylase (DBH) is responsible for maintaining dopamine-to-norepinephrine ratio implicated in migraine pathophysiology. Therefore, we aimed to look for association of functional variants in ANKK1 (rs1800497), DRD2 (rs6275 and rs1799732) and DBH (rs7239728 and rs1611115) genes with migraine susceptibility. The present study was carried out in two dependent cohorts (n primary = 208, n secondary = 127, n controls = 200). The results of the cohorts were pooled by meta-analysis using Fisher's and Mantel-Haenszel test. Benjamini-Hochberg false discovery rate test was used to correct for multiple comparisons. Computer algorithm-based TANGO, WALTZ and LIMBO predictions were used to evaluate the effect of missense polymorphism (rs1800497). For ANKK1 polymorphism, variant genotype and allele showed significant associations with migraine risk. A significant protective effect of variant DRD2 rs6275 polymorphism was noticed. DBH rs7239728 imparted significant risk at genotypic, allelic and carrier analyses. We identified a risk haplotype in DRD2 loci. Two genotype interactions between ANKK1rs1800497 and DBHrs72393728 polymorphisms showed significant risks. The variant gene product of ANKK1 rs1800497 was predicted with decreased aggregation of ANKK1 protein. In conclusion, we identified novel genetic variants, haplotype and gene interactions in dopaminergic pathway as potential risk factors for migraine susceptibility.