Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression

Ewoud Ewing, Lara Kular, Sunjay J Fernandes, Nestoras Karathanasis, Vincenzo Lagani, Sabrina Ruhrmann, Ioannis Tsamardinos, Jesper Tegner, Fredrik Piehl, David Gomez-Cabrero, Maja Jagodic

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Multiple Sclerosis (MS) is a chronic inflammatory disease and a leading cause of progressive neurological disability among young adults. DNA methylation, which intersects genes and environment to control cellular functions on a molecular level, may provide insights into MS pathogenesis. We measured DNA methylation in CD4+ T cells (n = 31), CD8+ T cells (n = 28), CD14+ monocytes (n = 35) and CD19+ B cells (n = 27) from relapsing-remitting (RRMS), secondary progressive (SPMS) patients and healthy controls (HC) using Infinium HumanMethylation450 arrays. Monocyte (n = 25) and whole blood (n = 275) cohorts were used for validations. B cells from MS patients displayed most significant differentially methylated positions (DMPs), followed by monocytes, while only few DMPs were detected in T cells. We implemented a non-parametric combination framework (omicsNPC) to increase discovery power by combining evidence from all four cell types. Identified shared DMPs co-localized at MS risk loci and clustered into distinct groups. Functional exploration of changes discriminating RRMS and SPMS from HC implicated lymphocyte signaling, T cell activation and migration. SPMS-specific changes, on the other hand, implicated myeloid cell functions and metabolism. Interestingly, neuronal and neurodegenerative genes and pathways were also specifically enriched in the SPMS cluster. We utilized a statistical framework (omicsNPC) that combines multiple layers of evidence to identify DNA methylation changes that provide new insights into MS pathogenesis in general, and disease progression, in particular. FUND: This work was supported by the Swedish Research Council, Stockholm County Council, AstraZeneca, European Research Council, Karolinska Institutet and Margaretha af Ugglas Foundation.
Original languageEnglish (US)
Pages (from-to)411-423
Number of pages13
StatePublished - Apr 30 2019

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: Acknowledgements: The authors would like to thank Dr. Y. Liu and Dr. A. Feinberg for provision of a part of the raw data and Dr. H. Morikawa for his input during data analysis. Funding: This study was supported by grants from the Swedish Research Council (MJ, FP, JT), the Swedish Association for Persons with Neurological Disabilities (MJ), the Swedish Brain Foundation (MJ, JT), the Stockholm County Council - ALF project (MJ, FP), AstraZeneca - AstraZeneca-Science for Life Laboratory collaboration (MJ, FP, JT), StratNeuro (JT), STATEGRA FP7 (JT), the European Research Council (FP/2007-2013)/ERC Grant Agreement n. 617393; CAUSALPATH (IT, VL) and Karolinska Institute's funds (MJ). L. Kular is supported by a fellowship from the Margaretha af Ugglas Foundation.


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