In recent years, viruses have been identified as culprits in neurodegenerative diseases. Epidemiological studies have shown a compelling link between the Epstein–Barr virus (EBV) and the development and pathogenesis of multiple sclerosis (MS). However, the causal gene variants linking the virus to disease remain unknown. New research published in G3:​Genes|Genomes|Genetics identify potential risk alleles in the regulatory regions of B-cells derived from MS patients1.

EBV infection and multiple sclerosis

MS is a chronic immune-mediated neurological disorder characterized by demyelination and progressive neurodegeneration. Since it has become clear that Epstein-Barr virus infection increases MS risk to 32-fold2 and EBV interacts with MS genetic risk variants to drive the disease3, researchers are interested in identifying alleles responsible for MS development and pathogenesis after infection.     

While MS is a disease of the central nervous system, the majority of disease risk genes identified in genome-wide association studies are immune-related, mostly expressed in B cells, T cells, and/or monocytes. B cells are of particular interest because they get infected by EBV and serve as a reservoir for latent EBV. Further, known MS genetic variants are typically found in noncoding regions. Therefore, Granitto et al. systematically assessed enhancer and silencer dynamics in B cells in MS. 

Identifying disease-specific variants

The researchers first generated EBV-transformed B cell lines from two patients with MS and measured transcription activity in them using Massively Parallel Reporter Assays (MPRAs). MPRA is a quantitative assay that allows functional measurement of thousands of candidate regulatory sequences simultaneously using RNA sequencing. 

The scientists identified numerous allelic enhancing and silencing variants representing several known MS risk loci. Many variants were also different between the patients, highlighting genotype-dependent variation in disease gene expression. They also identified many of these variants present in EBV-infected B cells from healthy controls, suggesting infection-related transcriptional changes. Lastly, Granitto et al. performed expression quantitative trait loci (eQTL) analysis, identifying genes that contribute to dysregulated B-T cell interactions, cytokine production, and antigen presentation; all the pathways with known contributions in the development and pathogenesis of MS.

Overall, these results demonstrate a complex regulatory interplay between enhancing and silencing variants at MS risk loci and show how these variants might be linked to EBV infection.

References

  • Genome-wide discovery of multiple sclerosis genetic risk variant allelic regulatory activity

    Marissa Granitto, Lois Parks, Molly S Shook, Carmy Forney, Xiaoting Chen, Lee E Edsall, Omer A Donmez, Sreeja Parameswaran, Kristen S Fisher, Aram Zabeti, Lucinda P Lawson, Matthew T Weirauch, Leah C Kottyan

    G3 Genes|Genomes|Genetics. November 2025. 15(11).

    DOI: 10.1093/g3journal/jkaf192

    Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

    Kjetil Bjornevik, Marianna Cortese, Brian C Healy, Jens Kuhle, Michael J Mina, Yumei Leng, Stephen J Elledge, David W Niebuhr, Ann I Scher, Kassandra L Munger, and Alberto Ascherio

    Science 375,296-301(2022).

    DOI:10.1126/science.abj8222

    Gene-Environment Interactions in Multiple Sclerosis: A UK Biobank Study

    Benjamin Meir Jacobs, Alastair J Noyce, Jonathan Bestwick, Daniel Belete, Gavin Giovannoni, Ruth Dobson

    Neurol Neuroimmunol Neuroinflamm. 2021 May 28;8(4):e1007.

    DOI: 10.1212/NXI.0000000000001007

Sejal Davla is a freelance science writer and data scientist with expertise in neuroscience and genetics. She is a motivated storyteller and works on projects at the intersection of science, data, and policy.

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