Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms

Nina L. Fransen, Jakob B.A. Crusius, Joost Smolders, Mark R. Mizee, Corbert G. van Eden, Sabina Luchetti, Ester B.M. Remmerswaal, Jörg Hamann, Matthew R.J. Mason, Inge Huitinga*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Scopus)
16 Downloads (Pure)


Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease-relevant mechanisms. Building on our recent work showing the association of clinical disease course with post-mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology-associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T-allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis.

Original languageEnglish
Pages (from-to)106-119
Number of pages14
JournalBrain Pathology
Issue number1
Early online date22 Jun 2019
Publication statusPublished - Jan 2020
Externally publishedYes

Bibliographical note

Funding Information:
The data that support the findings of this study are available from the corresponding author upon reasonable request. The data used for the analyses described in this manuscript were obtained from: GTEx Analysis Release V7 (dbGaP Accession phs000424.v7.p2) the GTEx Portal on 30‐5‐2018. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Publisher Copyright:
© 2019 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology


Dive into the research topics of 'Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms'. Together they form a unique fingerprint.

Cite this