Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progressionResearch in context
Ewoud Ewing,
Lara Kular,
Sunjay J. Fernandes,
Nestoras Karathanasis,
Vincenzo Lagani,
Sabrina Ruhrmann,
Ioannis Tsamardinos,
Jesper Tegner,
Fredrik Piehl,
David Gomez-Cabrero,
Maja Jagodic
Affiliations
Ewoud Ewing
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17177, Sweden
Lara Kular
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17177, Sweden
Sunjay J. Fernandes
Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 17177, Sweden; Science for Life Laboratory, Solna, Sweden
Nestoras Karathanasis
Institute of Computer Science, Foundation for Research and Technology-Hellas, Heraklion, Greece; Computational Medicine Center, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
Vincenzo Lagani
Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia; Gnosis Data Analysis PC, Heraklion, Greece
Sabrina Ruhrmann
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17177, Sweden
Ioannis Tsamardinos
Gnosis Data Analysis PC, Heraklion, Greece; Department of Computer Science, University of Crete, Heraklion, Greece
Jesper Tegner
Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 17177, Sweden; Biological and Environmental Sciences and Engineering Division, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Saudi Arabia; Science for Life Laboratory, Solna, Sweden
Fredrik Piehl
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17177, Sweden; Center for Neurology, Academic Specialist Clinic, Stockholm Health Services, Stockholm, Sweden
David Gomez-Cabrero
Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 17177, Sweden; Translational Bioinformatics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain; Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, UK
Maja Jagodic
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17177, Sweden; Corresponding author at: CMM, L8:04, Karolinska University Hospital, 17176 Stockholm, Sweden.
Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Keywords: DNA methylation, Epigenetics, Multiple sclerosis, Immune cells, Secondary progressive multiple sclerosis, Relapsing-remitting multiple sclerosis, 450 K, EPIC, omicsNPC