Are Epigenetic Factors Implicated in Chronic Widespread Pain?

PLoS One. 2016 Nov 10;11(11):e0165548. doi: 10.1371/journal.pone.0165548. eCollection 2016.


Background: Chronic widespread musculoskeletal pain (CWP) is the cardinal symptom of fibromyalgia and affects about 12% of the general population. Familial aggregation of CWP has been repeatedly demonstrated with estimated heritabilities of around 50%, indicating a genetic susceptibility. The objective of the study was to explore genome-wide disease-differentially methylated positions (DMPs) for chronic widespread pain (CWP) in a sample of unrelated individuals and a subsample of discordant monozygotic (MZ) twins.

Methodology/principle findings: A total of N = 281 twin individuals from the TwinsUK registry, including N = 33 MZ twins discordant for self-reported CWP, were part of the discovery sample. The replication sample included 729 men and 756 women from a subsample of the KORA S4 survey-an independent population-based cohort from Southern Germany. Epigenome-wide analysis of DNA methylation was conducted using the Illumina Infinium HumanMethylation 450 DNA BeadChip in both the discovery and replication sample. Of our 40 main loci that were carried forward for replication, three CPGs reached significant p-values in the replication sample, including malate dehydrogenase 2 (MDH2; p-value 0.017), tetranectin (CLEC3B; p-value 0.039), and heat shock protein beta-6 (HSPB6; p-value 0.016). The associations between the collagen type I, alpha 2 chain (COL1A2) and monoamine oxidase B (MAOB) observed in the discovery sample-both of which have been previously reported to be biological candidates for pain-could not be replicated.

Conclusion/significance: Our results may serve as a starting point to encourage further investigation in large and independent population-based cohorts of DNA methylation and other epigenetic changes as possible disease mechanisms in CWP. Ultimately, understanding the key mechanisms underlying CWP may lead to new treatments and inform clinical practice.

MeSH terms

  • Aged
  • Chronic Pain / genetics*
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Female
  • Fibromyalgia / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • HSP20 Heat-Shock Proteins / genetics
  • Humans
  • Lectins, C-Type / genetics
  • Malate Dehydrogenase / genetics
  • Male
  • Middle Aged
  • Musculoskeletal Pain / genetics*
  • Polymorphism, Single Nucleotide
  • Twins, Monozygotic


  • HSP20 Heat-Shock Proteins
  • HSPB6 protein, human
  • Lectins, C-Type
  • tetranectin
  • MDH2 protein, human
  • Malate Dehydrogenase