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Background The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache. Methods Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis. Results None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways. Conclusion In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease. [ABSTRACT FROM AUTHOR]

Background: There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) shouldbe considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migrainecases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differfrom male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, weexamined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 populationmatchedcontrols.Methods: Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migrainesubgroups was performed for the 12 independent SNP loci significantly associated (p<5x10-8; thus surpassing thethreshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNPeffect concordance analysis (SECA) at over 23,000 independent SNPs.Results: Significant heterogeneity of SNP effects (phet<1.4x10-3) was observed between the MA and MO subgroups(for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 andrs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genomewideSNP effects to be in the same direction across the subgroups.Conclusions: Any differences in common genetic risk across these subgroups are outweighed by the similarities. Metaanalysisof additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibilityloci for migraine. [ABSTRACT FROM AUTHOR]

Introduction: It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related.Aim: Using a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO.Methods: Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO.Results: We found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value (pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) (pbinomial-test = 1.5 × 10(-4)). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue.Conclusions: Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both types of migraine. [ABSTRACT FROM AUTHOR]