Polygenic Risk Scores and the Lifetime Risk of Multiple Sclerosis: Insights from a Population-Based Birth-Year Cohort
Multiple sclerosis (MS) is a complex immune-mediated disease of the central nervous system with a multifactorial etiology that includes both environmental and genetic determinants. Although genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for MS, the extent to which these genetic factors shape lifetime risk rather than relative susceptibility has remained unclear. The study by Loonstra and colleagues addresses this gap by quantifying lifetime MS risk across the spectrum of polygenic risk in a population-based birth-year cohort from the Netherlands.
A Population-Based Birth-Year Cohort as a Methodological Innovation
A major strength of this work lies in its use of the Project Y cohort, which includes nearly all individuals with MS born in 1966 in the Netherlands. By anchoring analyses to a single birth year, the authors effectively minimized confounding by age, calendar period, and heterogeneous environmental exposures. Control participants were drawn from both the same birth-year cohort and the Amsterdam Dementia Cohort, ensuring age comparability. This design allowed the authors to move beyond odds ratios and directly estimate sex-specific lifetime risks of MS across genetic risk strata.
Construction and Interpretation of the Polygenic Risk Score
The polygenic risk score (PRS) was constructed using 215 genome-wide significant MS-associated variants derived from the largest MS GWAS to date. Variants were weighted by their log-transformed odds ratios and standardized across participants. Importantly, major histocompatibility complex (MHC) variants—known to exert disproportionate influence on MS susceptibility—were carefully imputed and incorporated. Participants were then stratified into deciles based on the PRS distribution among controls, enabling an interpretable comparison of genetic risk across the population.
Striking Gradients in Lifetime Risk Across Genetic Risk Deciles
The central finding of the study is the pronounced gradient in lifetime MS risk across PRS deciles. Among women in the highest 10% of genetic risk, approximately 1 in 92 developed MS over their lifetime, compared with only 1 in 2,700 among women in the lowest 30% of genetic risk. A similar, albeit lower absolute risk, pattern was observed in men, with lifetime risks ranging from 1 in 293 in the highest decile to approximately 1 in 7,900 in the lowest-risk group. These results demonstrate that common genetic variation exerts a substantial influence on absolute disease risk, not merely relative susceptibility.
Sex Differences in Absolute Risk but Not Genetic Effect Direction
Consistent with epidemiological data, women exhibited higher absolute lifetime risks of MS than men across all PRS deciles. However, the relative contrast between high-risk and low-risk genetic strata was comparable between sexes, with relative risks exceeding 25-fold. This indicates that while sex modifies baseline risk, the proportional contribution of polygenic burden to MS susceptibility is largely shared. The findings reinforce the importance of sex-stratified analyses when translating genetic risk into clinically meaningful estimates.
Polygenic Risk and Disease Course: A Clear Dissociation
Notably, the PRS showed no statistically significant association with age at symptom onset, age at secondary progression, or time to secondary progression after correction for multiple testing. These results support emerging evidence that the genetic architecture of MS susceptibility is largely distinct from that governing disease severity and progression. In other words, genetic variants that increase the likelihood of developing MS do not necessarily influence how early the disease manifests or how aggressively it progresses.
Clinical and Translational Implications of Lifetime Risk Estimation
From a translational perspective, this study reframes the potential utility of polygenic risk scores in MS. Rather than serving as predictors of disease course, PRSs may be most valuable in refining diagnostic probability. A very high PRS could increase diagnostic confidence in ambiguous cases, whereas an extremely low PRS may serve as a “red flag,” prompting clinicians to reconsider alternative diagnoses that mimic MS. While generalizability beyond European ancestry populations remains a limitation, this work represents a critical step toward integrating population-scale genetics into absolute risk estimation for complex neurological diseases.
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:
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.
