Redefining Genetic Risk: Polygenic Scores for Multiple Sclerosis in South Asian Populations
Polygenic risk scores (PRS) are a powerful tool in genetics, aggregating an individual's burden of risk alleles to estimate the overall genetic risk for specific traits or diseases. However, these scores often perform poorly across different ancestral groups, potentially reinforcing health disparities. This study addresses the performance of European-derived PRS in predicting multiple sclerosis (MS) in South Asian populations compared to European populations.
Methods
The study utilized data from two significant longitudinal genetic cohort studies:
1. Genes & Health (2015–present): This study focuses on around 50,000 British–Bangladeshi and British–Pakistani individuals.
2. UK Biobank (2006–present): Comprised of approximately 500,000 predominantly White British individuals.
The researchers compared individuals with and without MS in both studies (Genes & Health: 42 cases, 40,490 controls; UK Biobank: 2,091 cases, 374,866 controls). PRS were calculated using clumping and thresholding with risk allele effect sizes obtained from the largest MS genome-wide association study to date. Scores were calculated both including and excluding the major histocompatibility complex (MHC) region, which is the most influential locus in determining MS risk. The performance of PRS prediction was evaluated using Nagelkerke’s pseudo-R² metric, adjusted for case ascertainment, age, sex, and the first four genetic principal components.
Results
The findings highlighted that European-derived PRS significantly underperform in South Asian populations compared to European populations. This underperformance is critical, given the potential future clinical utility of PRS in predicting disease risk and guiding preventive measures. The study suggests that the discrepancies in PRS performance between ancestral groups need to be addressed to avoid exacerbating health inequalities.
Conclusion
This research underscores the necessity for developing ancestry-specific PRS to ensure equitable healthcare advancements. For PRS to be a reliable tool in clinical settings, particularly for diverse populations, there must be a concerted effort to include varied ancestral groups in genetic research. Future studies should focus on creating more inclusive PRS models to improve disease prediction accuracy and healthcare outcomes for all population groups.
Implications for Future Research
1. Inclusive Genetic Research: There is a pressing need to include a broader range of ancestral groups in genetic research to develop more accurate and inclusive PRS models.
2. Healthcare Equity: Addressing the underperformance of European-derived PRS in non-European populations is essential to prevent further health disparities.
3. Policy and Funding: Increased funding and policy support are necessary to encourage research that focuses on diverse populations and the development of equitable healthcare tools.
In summary, while PRS holds promise for predicting genetic risk and guiding preventive healthcare, their current limitations across different ancestral groups highlight the need for more inclusive and equitable genetic research practices.
Reference:
Breedon, J. R., Marshall, C. R., Giovannoni, G., van Heel, D. A., Dobson, R., & Jacobs, B. M. (2023). Polygenic risk score prediction of multiple sclerosis in individuals of South Asian ancestry. Brain Communications, 5(2), fcad041.
