The Role of Polygenic Risk Scores in Understanding Multiple Sclerosis Susceptibility and Phenotype in European Populations
Multiple sclerosis (MS) is a complex neurological disorder characterized by inflammation and damage to the central nervous system (CNS). Over the past decades, understanding MS’s genetic basis has been a significant focus of research, leading to the development of tools like the polygenic risk score (PRS). This score aggregates the effect of numerous genetic variants to estimate an individual’s genetic predisposition to MS. The recent study by Shams et al., published in Brain in 2023, sheds new light on how PRS can predict MS susceptibility and even its progression.
Unpacking the Polygenic Risk Score for Multiple Sclerosis
The study leveraged data from the largest genome-wide association study (GWAS) conducted to date, encompassing over 47,000 MS cases and more than 68,000 controls. From this massive dataset, a PRS was developed to predict MS risk among European populations. The PRS models constructed in this study accounted for both genome-wide and pathway-specific genetic risks, and their predictive accuracy was rigorously validated across several datasets, including the UK Biobank (UKBB) and the Kaiser Permanente in Northern California (KPNC).
Individuals in the top 10% of PRS values were shown to be at significantly higher risk of developing MS compared to those with median or low PRS. For example, those in the top decile had more than a five-fold increased risk in the UKBB cohort and a 15-fold increased risk in the KPNC cohort. These findings highlight the PRS’s value as a powerful tool for identifying individuals at elevated risk for MS.
Enhancing Risk Stratification Beyond Conventional Factors
While traditional risk factors for MS, such as age, sex, and environmental exposures (e.g., Epstein-Barr virus infection), contribute to disease prediction, adding PRS to these models significantly improves their predictive power. In the UKBB and KPNC cohorts, incorporating PRS into clinical risk models enhanced risk discrimination by up to 26%. This demonstrates the promise of PRS as a valuable addition to conventional risk factors in MS risk stratification.
Pathway-Specific Insights from PRS
One of the novel contributions of this study is the development of pathway-specific PRS, which allows for the dissection of genetic circuits underlying MS risk. The authors identified several immune-related pathways, such as interleukin signaling and T-cell receptor (TCR) pathways, as being significantly associated with MS susceptibility. This supports the long-held understanding that dysregulation of the immune system plays a critical role in MS pathogenesis.
Furthermore, pathways related to viral infection, oxidative stress, and epigenetic regulation emerged as contributors to MS risk. The involvement of viral infection pathways, such as those triggered by Epstein-Barr virus, aligns with previous evidence linking viral infections to MS onset.
PRS and Its Link to MS Progression
In addition to predicting MS susceptibility, the study also examined the association between PRS and markers of disease progression, such as thalamic atrophy. Thalamic volume loss is a hallmark of MS progression, and this study found a significant association between high PRS and thalamic atrophy, especially over a 10-year follow-up period. This suggests that genetic predisposition may also influence the severity of CNS damage in MS, adding another layer of insight into how PRS can inform disease prognosis.
Implications for Familial MS Risk
The study also explored PRS in familial MS cases, finding that siblings of MS patients with higher PRS were at increased risk of developing the disease. This is particularly useful in clinical settings for assessing risk within families, where knowledge of familial PRS could guide early monitoring and intervention strategies for unaffected relatives.
Moving Toward Personalized Risk Assessment and Treatment
The integration of PRS into MS risk models holds the potential for significant clinical applications. In high-risk individuals—such as those with a family history of MS or suggestive symptoms—PRS can help prioritize early intervention and guide treatment strategies. Given that MS often manifests between the ages of 20 and 40, early risk identification could be pivotal in delaying disease onset or reducing symptom severity through lifestyle modifications or preventive therapies.
Future Directions: Expanding PRS Research Beyond European Populations
While this study primarily focused on European populations, there is a growing need to expand PRS research to non-European populations, such as African Americans and Hispanic Americans. Doing so would help to ensure that PRS tools are globally applicable and effective in predicting MS risk across diverse genetic backgrounds.
In conclusion, the study by Shams et al. underscores the significant role that PRS can play in understanding MS susceptibility, disease progression, and familial risk. As genetic research continues to evolve, tools like PRS will become increasingly important in the early diagnosis and personalized management of complex diseases like MS.
References:
Shams, H., Shao, X., Santaniello, A., Kirkish, G., Harroud, A., Ma, Q., ... & Oksenberg, J. R. (2023). Polygenic risk score association with multiple sclerosis susceptibility and phenotype in Europeans. Brain, 146(2), 645-656.
