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

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.

Xavier, A., Maltby, V. E., Ewing, E., Campagna, M. P., Burnard, S. M., Tegner, J. N., Slee, M., Butzkueven, H., Kockum, I., Kular, L., Jokubaitis, V. G., Kilpatrick, T., Alfredsson, L., Jagodic, M., Ponsonby, A.-L., Taylor, B. V., Scott, R. J., Lea, R. A., & Lechner-Scott, J. (2023). DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes. International Journal of Molecular Sciences, 24(16), 12576. https://doi.org/10.3390/ijms241612576

This study was supported by the following funding bodies: NHMRC (AusLong) grant APP1127819, NMSS (AusImmune) grant RG-1803-30499, and MSRA (severity study) grant 18-0424. The authors acknowledge support from the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. The Ausimmune/AusLong investigators group: Robyn Lucas (National Centre for Epidemiology and Population Health, Canberra), Keith Dear (Duke Kunshan University, Kunshan, China), Ingrid van der Mei, Leigh Blizzard, Steve Simpson-Yap, Simon Broadley (Griffith University, Gold Coast, Australia), David Williams, Cameron Shaw and Caron Chapman (Barwon Health, Geelong, Australia), Alan Coulthard (University of Queensland, Brisbane, Australia), and Patricia Valery (QIMR Berghofer Medical Research Institute, Brisbane, Australia), as well as Terry Doyer and Michael Pender. The authors would also like to acknowledge Peri Noori and David Gomez-Cabrero for their contribution to the work on isolated B cells. Finally, the authors would like to thank all the pwMS and control subjects who participated in this research.


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