Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression
Name:
1-s2.0-S2352396419302816-main.pdf
Size:
3.885Mb
Format:
PDF
Description:
Published version
Name:
1-s2.0-S2352396419302816-mmc1.xlsx
Size:
25.17Kb
Format:
Microsoft Excel 2007
Description:
Supplemental files
Name:
1-s2.0-S2352396419302816-mmc2.xlsx
Size:
21.63Mb
Format:
Microsoft Excel 2007
Description:
Supplemental files
Name:
1-s2.0-S2352396419302816-mmc3.xlsx
Size:
27.71Kb
Format:
Microsoft Excel 2007
Description:
Supplemental files
Name:
1-s2.0-S2352396419302816-mmc4.xlsx
Size:
1.256Mb
Format:
Microsoft Excel 2007
Description:
Supplemental files
Name:
1-s2.0-S2352396419302816-mmc5.xlsx
Size:
222.0Mb
Format:
Microsoft Excel 2007
Description:
Supplemental files
Name:
1-s2.0-S2352396419302816-mmc6.xlsx
Size:
25.96Kb
Format:
Microsoft Excel 2007
Description:
Supplemental files
Name:
1-s2.0-S2352396419302816-mmc7.xlsx
Size:
20.52Kb
Format:
Microsoft Excel 2007
Description:
Supplemental files
Name:
1-s2.0-S2352396419302816-mmc8.xlsx
Size:
1.218Mb
Format:
Microsoft Excel 2007
Description:
Supplemental files
Name:
1-s2.0-S2352396419302816-mmc9.docx
Size:
247.0Kb
Format:
Microsoft Word 2007
Description:
Supplemental files
Type
ArticleAuthors
Ewing, EwoudKular, Lara
Fernandes, Sunjay J
Karathanasis, Nestoras
Lagani, Vincenzo
Ruhrmann, Sabrina
Tsamardinos, Ioannis
Tegner, Jesper

Piehl, Fredrik
Gomez-Cabrero, David
Jagodic, Maja
KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Date
2019-04-30Online Publication Date
2019-04-30Print Publication Date
2019-05Permanent link to this record
http://hdl.handle.net/10754/652884
Metadata
Show full item recordAbstract
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.Citation
Ewing E, Kular L, Fernandes SJ, Karathanasis N, Lagani V, et al. (2019) Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression. EBioMedicine. Available: http://dx.doi.org/10.1016/j.ebiom.2019.04.042.Sponsors
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.Publisher
Elsevier BVJournal
EBioMedicineAdditional Links
https://www.sciencedirect.com/science/article/pii/S2352396419302816ae974a485f413a2113503eed53cd6c53
10.1016/j.ebiom.2019.04.042
Scopus Count
Except where otherwise noted, this item's license is described as This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).