Genetics of migraine: a systematic review and meta-analysis of 21 genes

Migraine is a common neurovascular disorder, typically characterized by recurrent unilateral headaches. Genetic factors play a significant role in its susceptibility. Over the past few decades, numerous candidate gene association studies have examined various genetic variants; however, their findings have often been inconsistent. In light of this, the purpose of this systematic review was to use a meta-analysis approach to identify the genetic risk factors that are associated with migraines. The protocol for this review was registered with PROSPERO (registration number: CRD42024501045). Following PRISMA guidelines, we conducted a pooled analysis of electronic database literature. Our approach included quality assessment, association analysis, and examination of publication bias and heterogeneity. We utilized the NOS tool, odds ratios (OR) with 95% confidence intervals, Begg's and Egger's tests, and χ2 based on Cochran's Q Test, along with I2 tests to ensure methodological rigor. The meta-analysis identified significant associations between migraine and multiple genetic variants, including rs4986938 (ESR2), G684A (NOTCH3), NcoI (DRD2), rs6318 (HTR2C), rs6166 (FSHR), 19bp Ins/Del (DBH), rs6265 (BDNF), rs10046 (CYP19A1), and rs3781719 (CALCA). These variants were classified into functional groups related to estrogen signaling, receptor activity, and neuropeptide regulation. Within the protein–protein interaction network, BDNF emerged as the central node, highlighting its pivotal role in molecular pathways contributing to migraine susceptibility. These findings underscore the genetic basis of migraine across different subtypes and populations, providing insights into its pathophysiology and suggesting potential avenues for personalized management strategies.