DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes

Alexandre Xavier, Vicki E. Maltby, Ewoud Ewing, Maria Pia Campagna, Sean M. Burnard, Jesper N. Tegner, Mark Slee, Helmut Butzkueven, Ingrid Kockum, Lara Kular, Ausimmune/AusLong Investigators Group, Vilija G. Jokubaitis, Trevor Kilpatrick, Lars Alfredsson, Maja Jagodic, Anne Louise Ponsonby, Bruce V. Taylor, Rodney J. Scott, Rodney A. Lea, Jeannette Lechner-Scott

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Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

Original languageEnglish
Article number12576
Number of pages20
JournalInternational Journal of Molecular Sciences
Issue number16
Publication statusPublished - 8 Aug 2023


  • cell deconvolution
  • epigenetics
  • epigenome-wide association studies
  • genetic risk
  • methylation
  • multiple sclerosis

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