Genetic Predictors of Multiple Sclerosis Severity: Insights from a Large Real-World Cohort Study
Multiple sclerosis (MS) is a heterogeneous neuroinflammatory and neurodegenerative disorder in which long-term disability progression varies widely between individuals. While genome-wide association studies (GWAS) have successfully identified more than 200 loci associated with MS susceptibility, translating genetic discoveries into predictors of disease severity and progression has proven considerably more challenging. Recently, large-scale GWAS efforts suggested that specific single-nucleotide variants (SNVs), particularly rs10191329A, may be associated with accelerated disability accumulation. The study by Kreft et al. critically examines whether these genetic findings have tangible clinical relevance when evaluated in a large, well-characterized, real-world cohort of people with MS.
Study Design and Cohort Characteristics
The investigators leveraged the South Wales Multiple Sclerosis Registry, a prospective cohort initiated in 1985 that includes longitudinal clinical, demographic, and treatment data. A total of 1,455 individuals with MS and available high-quality genotyping data were included, all meeting the 2017 McDonald diagnostic criteria. Importantly, disability outcomes were assessed using only physician-performed Expanded Disability Status Scale (EDSS) examinations, thereby minimizing measurement bias associated with interview-based scoring. This design allowed for robust assessment of long-term outcomes such as age-related MS severity score (ARMSS), time to EDSS milestones, relapse characteristics, and transition to secondary progressive MS.
Evaluation of rs10191329A as a Predictor of Disability
Contrary to prior GWAS findings, the study did not identify any meaningful association between the rs10191329A risk allele and MS disease severity. Across multiple analytical approaches—including linear regression, survival analysis, and genotype-stratified comparisons—the variant failed to predict ARMSS, age at onset, relapse rate, anatomical localization of disease activity, or progression to key disability milestones (EDSS 4, 6, or 8). Even an extremes-of-outcome analysis using propensity score–matched homozygous risk and non-risk carriers showed no difference in long-term disability trajectories. These findings suggest that rs10191329A does not provide clinically actionable prognostic information in routine MS care.
Polygenic Risk Scores and Their Limited Predictive Utility
The authors further explored whether aggregating genetic risk into polygenic risk scores (PRS) could enhance prediction of disease severity. Weighted genomic risk scores based on established MS susceptibility loci, as well as severity-focused PRS derived from prior GWAS, were evaluated. None of these scores correlated with ARMSS, age at onset, or time to disability milestones. This reinforces the concept that genetic architectures governing disease susceptibility and disease progression in MS are at least partially distinct, and that susceptibility loci alone do not explain interindividual differences in long-term neurodegeneration.
Replication of Suggestive Severity-Associated Variants
While the primary genome-wide significant variant could not be replicated, the study successfully validated two suggestive SNVs previously identified by the MSBase consortium—rs7289446G and rs868824C—as being modestly associated with sustained disability. Although effect sizes were small, the direction of association was consistent with prior reports. These findings highlight the importance of replication across independent cohorts and suggest that some genetic contributors to MS severity may exist, albeit with limited individual predictive power.
Role of HLA-DRB1*1501 in Disease Onset and Severity
The human leukocyte antigen allele HLA-DRB1*1501, long recognized as a major MS susceptibility factor, was also examined. Consistent with previous studies, the allele was associated with a younger age at disease onset but not with long-term disability severity. This distinction underscores the multifactorial nature of MS progression, in which early disease initiation does not necessarily translate into more aggressive long-term outcomes. Importantly, no interaction between genotype and disease-modifying treatment exposure was observed, suggesting that current therapies do not differentially modify genetic risk effects on progression.
Clinical Implications and Future Directions
Overall, this study provides compelling evidence that current MS severity genotypes, including rs10191329A, lack sufficient effect size and consistency to inform individualized prognostication or treatment decisions. The findings emphasize the necessity of cautious interpretation of GWAS results and the critical role of independent replication in complex neurodegenerative diseases. While genetic studies remain invaluable for elucidating biological pathways underlying MS progression, their immediate clinical utility remains limited. Future research will likely require integration of genetics with biomarkers, imaging, and longitudinal clinical data to meaningfully improve prediction of disease course and guide personalized management strategies.
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:
Kreft, K. L., Uzochukwu, E., Loveless, S., Willis, M., Wynford‐Thomas, R., Harding, K. E., ... & Robertson, N. P. (2024). Relevance of multiple sclerosis severity genotype in predicting disease course: a real‐world cohort. Annals of Neurology, 95(3), 459-470.
