Multiscale networks in multiple sclerosis

Abstract

Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information, and Boolean simulations identified paths within and among all layers. The path more commonly found from the boolean simulations connects MP2K, with Th17 cells, the retinal nerve fiber layer (RNFL) thickness and the age related MS severity score (ARMSS). Combinations of several proteins (HSPB1, MP2K1, SR6, KS6B1, SRC, MK03, LCK and STAT6)) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/530153v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@7dd26org.highwire.dtl.DTLVardef@482239org.highwire.dtl.DTLVardef@1bef03borg.highwire.dtl.DTLVardef@8dc6e6_HPS_FORMAT_FIGEXP M_FIG C_FIG Author SummaryComplex diseases such as Multiple Sclerosis (MS) involve the contribution of a wide range of biological processes. We conducted a systems biology study of MS based on network analysis and deep phenotyping in a prospective cohort of patients with clinical, imaging, genetics, and omics assessments. The gene, proteins and cell paths explained variation in central nervous system damage, and in metrics of disease severity. Such multilayer paths explain the different phenotypes of the disease and can be developed as biomarkers of MS.