title: Epigenetic DNA methylation changes associated with headache chronification: A retrospective case-control study.
abstract: 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.
authors.affiliation: 1 FORMI and Department of Neurology, Oslo University Hospital, Oslo, Norway.|2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Bendik S
authors.initials: BS
authors.lastname: Winsvold
authors.affiliation: 3 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|4 Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Priit
authors.initials: P
authors.lastname: Palta
authors.affiliation: 5 Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Else
authors.initials: E
authors.lastname: Eising
authors.affiliation: 2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|6 Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Page
authors.affiliation: 5 Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.|7 Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Arn Mjm
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: 3 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|8 Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA.|9 Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, USA.|10 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA.|11 Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA.|12 Department of Neurology, Massachusetts General Hospital, Boston, USA.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: 1 FORMI and Department of Neurology, Oslo University Hospital, Oslo, Norway.|2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: John-Anker
authors.initials: JA
authors.lastname: Zwart
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D020773:Headache Disorders / Q000235:genetics*; D006801:Humans; D012189:Retrospective Studies; D055815:Young Adult
keywords: Chronic headache; cohort studies; epigenetics