Genes, Brains, and the Future of MS Care: Unlocking the Genetics of Risk and Progression

Multiple sclerosis (MS) is one of medicine’s most puzzling disorders—an unpredictable disease in which the body’s own immune system attacks the central nervous system. Some people experience only mild relapses for decades, while others face rapid disability progression. Why this variability? Part of the answer may lie hidden in our DNA.

A recent review by Sahi and colleagues in Neurology (2025) explores how genetics shapes not only the risk of developing MS, but also how severe the disease becomes over time. Their work highlights both major breakthroughs and ongoing challenges in translating genetic discoveries into clinical insight.

From Family Clues to 230+ Risk Genes
MS is not a “genetic disease” in the way cystic fibrosis or Huntington’s are—there’s no single faulty gene that seals a person’s fate. Still, family studies revealed long ago that genetics matters: identical twins are far more likely to both develop MS than non-identical twins.

The first strong genetic signal emerged in the 1970s: HLA-DRB1*1501, an immune-related gene in the major histocompatibility complex. This allele remains the single strongest risk factor for MS, helping explain why the immune system mistakenly turns on the brain and spinal cord.

Fast-forward to today, and large international collaborations have identified over 230 genetic variants linked to MS risk. Most of them implicate the immune system, especially T cells and B cells. Together, these variants account for roughly 20% of MS heritability—meaning many other factors, from environment to chance, are also at play.

Genetics of Severity: A New Frontier
Interestingly, the very genes that predispose someone to MS don’t necessarily predict how aggressive the disease will be. Here lies one of the field’s biggest puzzles.

Recent genome-wide association studies (GWAS) have started to uncover genetic factors tied specifically to disease severity. The landmark finding: rs10191329, a variant near the DYSF-ZNF638 gene region. Carriers of this variant are more likely to experience faster disability progression, greater brain atrophy, and earlier need for mobility aids. Unlike risk genes, these severity-linked variants tend to be active in the central nervous system (CNS) itself, pointing toward pathways of neurodegeneration and repair rather than just immune attack.

This distinction suggests that MS risk and severity are guided by partially separate genetic architectures—one immune-driven, the other CNS-driven.

Why Replication is Hard
Science thrives on reproducibility, but confirming MS severity genes hasn’t been easy. Several studies have failed to replicate rs10191329’s impact, often due to small sample sizes, differences in how disability was measured, or variations in treatment availability across cohorts.

For example:

Some cohorts studied patients early in the disease, when neurodegeneration is less apparent.

Others used different severity metrics, such as longitudinal averages versus endpoint disability.

Treatment exposure (like early use of high-efficacy drugs) also complicates genetic signals.

These hurdles highlight how complex traits like MS progression cannot be explained by genetics alone—environment, lifestyle, and even random biological events all weave into the picture.

Beyond Disability: Looking “Beneath the Surface”
Most genetic studies measure severity using the Expanded Disability Status Scale (EDSS), which mainly reflects mobility. But MS is much more than walking ability. Cognitive decline, vision changes, and fatigue are often overlooked.

The authors argue that next-generation phenotyping—combining MRI markers (e.g., brain atrophy, gray matter damage), cognitive assessments, and patient-reported outcomes—will be key to uncovering the full genetic story of MS severity.

The Road Ahead: Diversity, Rare Variants, and Gene-Environment Interactions
The review underscores several future directions:

Ethnic diversity: Nearly all MS genetics studies so far have focused on Europeans. Expanding to diverse populations will reveal whether severity variants are universal or population-specific.

Rare variants: Whole-genome sequencing could capture rare but high-impact variants missed by GWAS.

Gene-environment interplay: For instance, smoking worsens MS outcomes, and some genetic variants amplify this risk. Understanding such interactions could point to personalized lifestyle interventions.

Pathway-based approaches: Instead of chasing single variants, studying whole gene networks may better capture the biology of progression.

Why This Matters
For patients, genetic insights could eventually mean better prediction tools: Who is likely to develop aggressive MS? Who will respond to certain therapies? For researchers, these findings provide new therapeutic targets, particularly in progressive MS, where current treatments remain limited.

But as Sahi et al. emphasize, genetics is just one piece of the MS puzzle. To unlock its clinical power, we’ll need bigger studies, deeper phenotyping, and integration with environment, lifestyle, and biology across the disease spectrum.

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:
Boutitah-Benyaich, I., Eixarch, H., Villacieros-Álvarez, J. et al. Multiple sclerosis: molecular pathogenesis and therapeutic intervention. Sig Transduct Target Ther 10, 324 (2025). https://doi.org/10.1038/s41392-025-02415-4