Selectivity in Genetic Association with Sub-classified Migraine in Women

Abstract

Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

“…The other genetic variants are predominantly expressed in the brain, mainly exert their effects through synaptic and neuronal regulation (Anttila et al 2013; Eising et al 2013a) and thus may contribute to the neuronal hyperexcitability of the migraine brain. In addition, it has been demonstrated that these genetic variants, with the exception of TRPM8 , show different and unique association patterns with additional migraine features, such as nausea, photophobia or aggravation by physical activity, which suggests that genetic variants play a divergent pathophysiological role in the development of migraine (Chasman et al 2014; Zameel Cader 2013), similar to our finding.…”

Emerging Genomic Biomarkers In Migraine

“…Additionally a population-based GWAS reported single nucleotide polymorphisms (SNPs) and susceptibility loci for migraine including one novel locus supporting existing concepts of the glutamergic homestasis involvement in migraine [10]. Although the role of glutamate in aura causing CSD has been further evidenced in functional studies of FHM mutations in cellular and animal models, the function of FHM genes in the headache phase of MA is elusive.…”

“…Genetic epidemiological studies undertaken over the last few decades have shown that significant genetic factors underlie both the rare and common forms of migraine [10][11][12]. However, attempts to successfully understand this genetic basis have been inconsistent owing to the multifactorial mode of inheritance, polygenic determination and the compounding influence of environmental factors in migraine [13].…”

Migraine Susceptibility Genes in Han Chinese of Fujian Province

“…In addition, several factors are known to influence migraine, such as family history, frequency, duration, pulsing pain, laterality, photophobia, nausea, and aggravation by physical activity 13. We did not assess the relationships of the SNPs evaluated in this study with these migraine-associated characteristics.…”