Unlocking the Genetics of Multiple Sclerosis: How New Discoveries Are Shaping the Future of MS Progression and Care
In recent years, multiple sclerosis (MS) research has undergone a dramatic shift. Once viewed as primarily an autoimmune disease driven by environmental triggers, MS is now recognized as a condition with a substantial—but complex—genetic architecture. As highlighted in Sahi et al., 2025, over 230 genetic variants have been mapped that influence susceptibility to MS, implicating the peripheral immune system as the key determinant of who develops the disease. Yet susceptibility is only half the story. Why do some people progress slowly while others accumulate disability rapidly? This review article tackles that question by dissecting the genetic influences not just on risk but on disease severity, representing a major step toward individualized MS prognosis.
From Susceptibility to Polygenicity: Why Risk Isn’t Destiny
While MS is not inherited in a classical Mendelian fashion, family and twin studies attest to a meaningful genetic contribution: monozygotic twins show 24–30% concordance, compared to just 3–5% in dizygotic twins. Crucially, risk is polygenic—most people, including healthy individuals, carry over 160 MS-associated alleles. The most influential susceptibility gene, HLA-DRB1*1501, clearly lowers age at onset and intensifies early inflammatory activity, but does not reliably predict long-term disability progression. As the article emphasizes, susceptibility variants explain only ~19% of heritable risk, and their effects are additive, modest, and intertwined with environmental exposures such as smoking, EBV, and vitamin D.
Why Predicting Severity Has Been So Difficult
For decades, researchers struggled to identify genetic variants linked to severity. One reason is methodological: disability measures like EDSS fluctuate and do not cleanly separate relapse-driven worsening from progression independent of relapse activity (PIRA). Figure 1 on page 7 demonstrates how two patients can show similar median ARMSS scores despite vastly different disease trajectories—one relapse-heavy, one slowly progressive. These measurement limitations have made earlier genome-wide association studies (GWAS) underpowered, leading mostly to “suggestive” rather than definitive variants.
The Breakthrough: rs10191329, the First Replicated Severity Variant
The turning point arrived with large multinational GWAS efforts. The International MS Genetics Consortium (IMSGC) identified the first genome-wide significant MS severity variant, rs10191329, located near DYSF–ZNF638, across a discovery cohort of 12,584 and replication cohort of 9,805 individuals. Carriers of the A risk allele showed higher ARMSS scores, faster EDSS progression, and reached the need for a walking aid (EDSS 6.0) 3.7 years earlier on average. Pathology data from autopsy tissue (Table 4) showed striking biological effects: A-allele homozygotes had 1.83× more brainstem lesions and 1.76× more cortical lesions, along with microglial activation and neuroaxonal injury—providing biological plausibility for the variant’s impact on disability accumulation.
Relapse Genetics and Pharmacogenetics: Smaller But Important Steps
In addition to severity, other genetic contributions are emerging. Variants such as rs12988804 (LRP2) and the low-frequency rs11871306 (WNT9B) are associated with higher relapse risk (HR ≈ 2.1) across multiple cohorts. These findings hint at underlying pathways governing relapse susceptibility distinct from those driving progression. Meanwhile, in pharmacogenetics, rs9828519 in SLC9A9 has been linked to poor response to interferon-β therapy—one of the first reproducible steps toward personalized DMT selection. Though not yet ready for routine care, these discoveries lay the foundation for treatment-tailored genomics.
Why Replication Has Been Hard—and What the Failures Teach Us
Despite the success of rs10191329, many severity-associated variants fail to replicate (Table 5). The article points to several reasons:
Statistical underpowering, because the effect sizes are small and risk-allele homozygotes are rare.
Differences in cohort composition, especially treatment exposure, age, and disease duration.
Environmental confounders, such as smoking or access to high-efficacy therapies.
Heterogeneous definitions of disability, such as using median vs. endpoint ARMSS, which Figure 1 shows can dramatically alter interpretation.
These limitations suggest that future MS genetics must be integrated with richer phenotyping—including MRI biomarkers, cognitive measures, and patient-reported outcomes.
The Road Forward: Diverse Genomes, Rare Variants, and Causality
The article concludes with a roadmap for the next decade of MS genetics. Increasing ancestral diversity is critical, as nearly all major MS GWAS to date have been restricted to European ancestry. Cross-ancestry analyses can improve fine-mapping and reveal population-specific severity loci. Additionally, whole-genome and exome sequencing will be essential to uncover rare, high-impact variants that conventional GWAS miss. Finally, causal inference tools—gene-based tests, pathway analyses, and Mendelian randomization—will be crucial for distinguishing meaningful biological drivers from statistical noise. Only through such comprehensive approaches can genetic insights be translated into individualized prognostic models and, ultimately, new therapeutic strategies for progressive MS.
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:
Sahi, N., Ciccarelli, O., Houlden, H., & Chard, D. T. (2025). Unlocking Multiple Sclerosis Genetics: From Susceptibility to Severity. Neurology, 105(8), e214141.
