Decoding MS Risk: How Hidden Genetic “Switches” Shape the Disease

Multiple sclerosis (MS) is a chronic immune-mediated disease in which the body’s own immune system attacks the protective myelin sheath around nerve fibers in the brain and spinal cord. This leads to progressive neurological symptoms, from vision problems and fatigue to paralysis in severe cases. Despite decades of research, the exact causes of MS remain elusive.

We know two things with relative certainty:

MS arises from a mix of environmental and genetic risk factors, and

One virus—Epstein-Barr virus (EBV)—is strongly implicated as a trigger.

But genetics contributes significantly. Large-scale genome-wide association studies (GWAS) have identified over 230 genetic risk loci linked to MS. The catch? Most of these risk variants fall in noncoding regions of the genome—areas that don’t make proteins but instead regulate when and how genes are switched on or off. That’s where the new study by Granitto and colleagues (2025) comes in.

Cracking Open the Noncoding Genome
The research team set out to answer a pressing question: Which MS genetic risk variants actually change how genes behave?

To do this, they used a powerful technology called the Massively Parallel Reporter Assay (MPRA). Think of it as a way to test thousands of genetic “switches” at once. Each candidate DNA sequence is linked to a reporter gene (in this case, GFP), introduced into cells, and then measured to see if it turns gene activity up (enhancer) or down (silencer).

The team analyzed 14,275 genetic variants across 217 established MS risk loci (plus hundreds more with suggestive links). Importantly, they carried out these tests not just in a standard lab B cell line (GM12878), but also in EBV-transformed B cells derived from MS patients. Since EBV infects B cells and B cells play a central role in MS pathology, this was a highly disease-relevant choice.

What They Found
The results were striking:

Over one-third of known MS risk loci showed clear regulatory activity.

They identified 150 allelic enhancers and 286 allelic silencers—variants where different versions of the same gene switch had distinct effects on gene activity.

These regulatory variants were tied to 83 independent MS risk loci.

Some key takeaways:
Many loci had both enhancer and silencer variants, hinting at complex genetic regulation.

Allelic enhancers were enriched for binding by transcriptional activators such as NFκB, EP300, and VDR.

Allelic silencers were enriched for chromatin remodelers like CBX5 and transcriptional repressors PAX5 and EGR1—proteins with known roles in B cell biology.

Pathway analysis linked these variants to antigen presentation, B-T cell interactions, and leukocyte cytotoxicity—all processes central to MS immune dysfunction.

Why It Matters
This study moves us a big step forward in understanding how genetic variation drives MS risk. Instead of just knowing where in the genome risk variants are, we now have functional data showing how these variants alter gene regulation.

Several broader implications emerge: Mechanistic Insight – The results support a model where genetic variants tweak B cell activity, antigen presentation, and cytokine signaling, ultimately promoting autoimmune attack in MS.

Gene-Environment Interaction – Since EBV infects B cells and hijacks many of the same regulatory circuits, the study provides a biological framework for how EBV and genetic risk may converge to trigger MS.

Therapeutic Potential – By pinpointing regulatory variants and their gene targets, this work highlights potential new pathways for drug development or precision therapies.

Caveats and Future Directions
As powerful as MPRA is, it’s not perfect. The assay uses artificial DNA constructs outside of their native chromatin environment, meaning some regulatory nuances may be missed. Also, the study focused only on B cells—important for MS, but not the only players. T cells, microglia, and other immune cells may also harbor critical regulatory variants.

Future studies using CRISPR-based genome editing in primary cells or organoid models will be needed to confirm which variants directly alter disease biology.

Conclusion
The Granitto et al. study represents one of the most comprehensive efforts to date to link MS genetic risk variants to functional gene regulation. By identifying hundreds of allelic enhancers and silencers across the MS genome, it lays a foundation for translating genetic associations into biological insight.

In short: MS is not just about “bad genes” but about how subtle changes in genetic switches shape immune cell behavior. Understanding these switches may one day allow us to flip them back—preventing or even reversing disease.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Granitto, M., Parks, L., Shook, M. S., Forney, C., Chen, X., Edsall, L. E., ... & Kottyan, L. C. (2025). Genome-wide discovery of multiple sclerosis genetic risk variant allelic regulatory activity. G3: Genes, Genomes, Genetics, jkaf192.