Addressing the Gaps: Polygenic Risk Scoring for Multiple Sclerosis Across Diverse Populations

In recent years, the role of genetics in complex diseases like Multiple Sclerosis (MS) has been increasingly highlighted, thanks to advances in genomic technologies. Polygenic Risk Scores (PRS), which aggregate the effects of numerous genetic variants into a single measure, have emerged as a powerful tool for predicting disease risk. However, a critical challenge remains: the applicability of these scores across diverse populations. A recent study by Rivier et al. (2024) takes a deep dive into this issue by evaluating the effectiveness of an MS-related PRS across European, African American, and Latino/admixed populations using data from the All of Us Research Program.

Understanding Polygenic Risk Scores in MS
Multiple Sclerosis is a chronic autoimmune disorder where the immune system mistakenly attacks the central nervous system, leading to a variety of neurological symptoms. The genetic underpinnings of MS are complex, with more than 300 single nucleotide polymorphisms (SNPs) identified as contributing to the disease. These SNPs, while individually associated with modest increases in risk, collectively influence susceptibility to MS. The PRS for MS aims to quantify an individual's cumulative genetic predisposition by summing the effects of these risk variants.

However, most genome-wide association studies (GWAS) that inform PRS development have been conducted in populations of European descent. This raises concerns about the validity and utility of these scores in other populations, particularly those with different genetic backgrounds.

Evaluating PRS Across Diverse Ancestries
Rivier and colleagues' study is grounded in the All of Us Research Program, an initiative aimed at accelerating biomedical research by including a diverse cohort of over one million Americans. This diversity is crucial for understanding how genetic tools like PRS perform across different ancestries.

The study focused on participants with whole genome sequencing data and electronic health records, allowing for a robust analysis of MS risk across European, African, and Latino/admixed populations. The researchers utilized a PRS based on 282 independent genetic variants associated with MS and stratified participants into quintiles based on their scores.

Key Findings: Disparities in PRS Performance
The study revealed significant disparities in the effectiveness of the PRS across the different populations:
European Population: The PRS effectively stratified MS risk among individuals of European ancestry, with those in the highest PRS quintile having a significantly higher risk of MS compared to those in the lowest quintile. This finding aligns with previous studies and underscores the robustness of the PRS in populations that closely match the original GWAS data.

Latino/Admixed Population: Similarly, the PRS was able to stratify risk in the Latino/admixed population, though the effect sizes were slightly smaller than in the European group. This suggests that while the PRS is still effective, the genetic architecture of MS in this population may differ slightly, warranting further investigation.

African Population: The PRS did not significantly stratify MS risk among individuals of African ancestry. This finding is particularly concerning as it highlights the limitations of using PRS developed from predominantly European datasets in other populations. The genetic diversity within African populations, combined with the underrepresentation of these groups in GWAS, likely contributes to this discrepancy.

Implications and the Need for Inclusive Research
The study by Rivier et al. underscores the importance of developing ancestry-specific PRS to ensure accurate and equitable risk prediction across all populations. The findings highlight the urgent need to include more diverse populations in genetic research, particularly in the development of PRS.

For individuals of African ancestry, the study suggests that the current PRS may not capture the full spectrum of genetic risk factors for MS, potentially leading to underestimation of disease risk. This limitation could have significant implications for clinical practice, where PRS are increasingly used to identify high-risk individuals and tailor prevention strategies.

Moving Forward: Enhancing Genetic Research Diversity
To address these challenges, future research must focus on expanding genetic studies to include a broader range of populations. This will not only improve the accuracy of PRS but also contribute to a more comprehensive understanding of the genetic basis of MS across different ancestries.

Moreover, there is a need to refine PRS methodologies to account for the unique genetic architecture and gene-environment interactions present in diverse populations. This includes developing new models that incorporate population-specific variants and environmental factors, ultimately advancing the goal of personalized medicine for all.

Conclusion
The study by Rivier et al. provides a critical evaluation of the effectiveness of MS-related PRS across different populations, revealing significant disparities that highlight the need for more inclusive genetic research. As we move toward a future where personalized medicine becomes the norm, ensuring that genetic tools like PRS are accurate and applicable across all populations will be key to reducing health disparities and improving outcomes for everyone.

This research serves as a call to action for the scientific community to prioritize diversity in genetic studies, ensuring that the benefits of genomic medicine are shared equitably across all populations.

References:
Rivier, C. A., Payabvash, S., Zhao, H. Y., Hafler, D. A., Falcone, G. J., & Longbrake, E. E. (2024). Differential Results of Polygenic Risk Scoring for Multiple Sclerosis in European and African American Populations. medRxiv, 2024-06.