The Role of Polygenic Risk Scores in Predicting Lifetime Risk of Multiple Sclerosis: A Population-Based Study

Multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system, has long been recognized for its complex interplay of genetic and environmental factors. The 2024 study by Loonstra et al. explores the predictive value of polygenic risk scores (PRS) in estimating the lifetime risk of MS. Using a population-based birth-year cohort from the Netherlands, this research marks a significant step forward in understanding how genetic predispositions can influence the likelihood of developing MS, particularly across different deciles of genetic risk.

Background: Genetic Architecture of MS
To date, over 200 genetic variants have been identified as contributing to MS susceptibility, though each variant individually has a relatively small effect. This study builds on previous work by aggregating these small-effect variants into a PRS, which represents a cumulative genetic risk score. PRSs are based on data from genome-wide association studies (GWAS), which have pinpointed various loci linked to MS in populations of European ancestry.

Despite advances in identifying MS-associated genetic variants, how these translate to a person's overall lifetime risk remains unclear. This study aimed to bridge that gap by evaluating the association between PRS deciles and the likelihood of developing MS in men and women.

Study Design: Population-Based Birth-Year Cohort
The authors used a comprehensive approach, identifying participants from the Project Y cohort, which included nearly all individuals born in the Netherlands in 1966. The study included both persons with MS (pwMS) and control participants, making it a robust dataset for investigating genetic risk. MS diagnoses were confirmed based on the 2010 or 2017 McDonald criteria, ensuring consistency in clinical definitions.

Participants’ genetic data were obtained using standard genotyping and imputation methods, allowing the calculation of MS-PRS. PRS deciles were created based on the distribution of genetic risk in the control participants, and the lifetime risk of MS was calculated for each decile.

Key Findings: Impact of PRS on Lifetime Risk of MS
One of the standout findings from this study was the marked difference in MS risk between the highest and lowest PRS deciles. Women in the top 10% genetic risk category had a lifetime risk of 1 in 92 (1.1%), while men in the same category had a risk of 1 in 293 (0.34%). Conversely, women and men in the lowest 30% genetic risk category had substantially lower risks—1 in 2,739 and 1 in 7,900, respectively.

The results indicate that genetic factors have a significant influence on the lifetime risk of developing MS. This suggests that a person’s PRS could be used as a potential tool for assessing their likelihood of developing the disease, particularly for those in the highest risk deciles.

No Significant Association with Disease Progression
Interestingly, the study found no significant association between the PRS and other key clinical variables, such as age at MS onset or time to secondary progression. This finding is consistent with earlier research, suggesting that the genetic architecture of MS risk differs from that of disease severity or progression. While a high PRS indicates an increased risk of developing MS, it does not appear to predict the course or severity of the disease.

Implications for Clinical Practice
The potential for using PRS as a clinical tool is significant. A high PRS could strengthen the case for diagnosing MS, particularly in patients with ambiguous symptoms. Conversely, a low PRS might serve as a red flag to investigate alternative diagnoses for conditions that mimic MS. This could be especially valuable in preventing misdiagnosis and ensuring that patients receive the appropriate treatments for their conditions.

Limitations and Considerations
While this study provides valuable insights, it is important to acknowledge its limitations. The results are specific to individuals of European ancestry, and the findings may not be generalizable to other populations. The PRS used in the study was derived from a GWAS of European individuals, and genetic risk factors for MS may vary in frequency and effect size across different ethnic groups.

Additionally, the study did not account for competing risks of death, which could influence the lifetime risk estimates. However, given the relatively young age of the cohort, the authors deemed this factor negligible.

Conclusion
The study by Loonstra et al. provides compelling evidence that polygenic risk scores can significantly influence the lifetime risk of developing multiple sclerosis, particularly in individuals with the highest genetic risk. While the PRS may not predict disease severity or progression, it holds promise as a valuable tool for clinicians assessing MS risk. Future research will be needed to explore the application of PRS in diverse populations and to further refine the use of genetic data in predicting MS risk.

References:
Loonstra, F. C., Álvarez Sirvent, D., Tesi, N., Holstege, H., Strijbis, E. M., Salazar, A. N., ... & Uitdehaag, B. (2024). Association of Polygenic Risk Score With Lifetime Risk of Developing Multiple Sclerosis in a Population-Based Birth-Year Cohort. Neurology, 103(7), e209663.