Single nuclei RNAseq stratifies multiple sclerosis patients into three distinct white matter glia responses

The lack of understanding as to the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies and biomarkers. Here, to address this gap, we analysed 740,000 single nuclei RNAseq profiles of 165 sample...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Macnair, Will, Calini, Daniela, Agirre, Eneritz, Bryois, Julien, Jaekel, Sarah, Kukanja, Petra, Stokar-Regenscheit, Nadine, Ott, Virginie, Foo, Lynette C, Collin, Ludovic, Schippling, Sven, Urich, Eduard, Nutma, Erik, Marzin, Manuel, Amor, Sandra, Magliozzi, Roberta, Heidari, Elyas, Robinson, Mark D, Ffrench-Constant, Charles, Castelo-Branco, Goncalo, Williams, Anna, Malhotra, Dheeraj
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 09.04.2022
Subjects
Biomarkers
Factor analysis
Gene expression
Lesions
Multiple sclerosis
Patients
Substantia alba
Substantia grisea
Online AccessGet full text

Cover

More Information
Summary:The lack of understanding as to the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies and biomarkers. Here, to address this gap, we analysed 740,000 single nuclei RNAseq profiles of 165 samples of white matter (WM) lesions, normal appearing WM, grey matter (GM) lesions and normal appearing GM from 55 MS patients and 28 controls. We find that gene expression changes in response to MS are highly cell-type specific in WM and GM lesions but are largely shared within an individual cell-type across lesions, following a continuum rather than discrete lesion-specific molecular programs. The major biological determinants of variability in gene expression in MS samples relate to individual patient effects, rather than to lesion types or other metadata. Using multi-omics factor analysis (MOFA+), we identify three subgroups of MS patients with distinct oligodendrocyte composition and WM glial gene expression signatures, suggestive of engagement of different pathological/regenerative processes. The discovery of these three patterns significantly advances our mechanistic understanding of progressive MS, provides a framework to use molecular biomarkers to stratify patients for best therapeutic approaches for progressive MS, and highlights the need for precision-medicine approaches to address heterogeneity among MS patients. Competing Interest Statement The study was funded by F. Hoffmann-La Roche Ltd. DM, DC, JB, WM, LF, LC, EU and SS are full time employees of F. Hoffmann-La Roche Ltd. The other authors declare no competing interests. Footnotes * https://gitlab.com/wmacnair/MS_lesions_snRNAseq * https://malhotralab.shinyapps.io/MS_broad/ * https://malhotralab.shinyapps.io/MS_fine/
DOI:10.1101/2022.04.06.487263