In recent years, viruses have been identified as culprits in neurodegenerative diseases. Epidemiological studies have shown a strong link between Epstein-Barr virus (EBV) and the development and pathogenesis of multiple sclerosis (MS). However, the causal gene variants linking the virus to disease are unknown. New research published in G3: Gene | Genomes | Genetics identifies potential risk alleles in regulatory regions of B cells derived from MS patients 1 .
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 the risk of MS by 32-fold 2 and that EBV interacts with MS genetic risk variants to drive the disease 3 , researchers are interested in identifying the alleles responsible for MS development and pathogenesis after infection.
Although 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 become infected with EBV and serve as reservoirs for latent EBV. Moreover, known MS genetic variants are commonly found in non-coding regions. Therefore, Granito ET may God bless him and grant him peace. Systematically evaluated effector 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 their transcriptional activity using massively parallel reporter assays (MPRA). MPRA is a quantitative assay that allows the functional measurement of thousands of candidate regulatory sequences simultaneously using RNA sequencing.
The scientists identified multiple allelic amplifications and silent variants representing several known MS risk loci. Many variants also differed between patients, highlighting genotype-dependent variability 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. Finally, Granito et al. Performed expression quantitative trait loci (EQTL) analysis, identifying genes that play important roles in BT cell interaction, cytokine production, and antigen presentation. All pathways with known contributions to MS development and pathogenesis.
Collectively, these results demonstrate a complex regulatory interplay between amplifying and silencing variants at MS risk loci and show how these variants can be linked to EBV infection.
References
Genome-wide discovery of allelic regulatory activity of multiple sclerosis genetic risk variants
Marisa Granito, Lois Parks, Molly S. Schock, Carmi Forney, Zhaoting Chen, Lee E. Edsall, Omar E. Donmez, Srija Premisoran, Kristen S. Fisher, Iram Zabetti, Lucinda P. Lawson, Matthew T. Werkach, Lake Cotten.
G3 Gene | Genomes | Genetics. November 2025. 15 (11).
doi: 10.1093/G3 Journal/jkaf192
Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis
Kjetel Bjornjevic, Mariana Cortesi, Brian C. Healy, Janice Kohl, Michael J. Mena, Yomi Lang, Stephen J. Alge, David W. Niebuhr, NI Scher, Cassandra L. Munger, and Alberto Escherio.
Science 375, 296-301 (2022).
doi: 10.1126/science.abj8222
Gene-environment interactions in multiple sclerosis: a UK biobank study
Benjamin Meyer Jacobs, Alastair J. Noyes, Jonathan Bestwick, Daniel Billett, Gavin Giovannini, Ruth Dobson
Neurol Neuroimmunol Neuroinflamm. 2021 May 28 8 8(4):E1007.
doi: 10.1212/nxi.0000000000001007
