Polygenic Risk Scores and the Lifetime Risk of Multiple Sclerosis: Insights from a Dutch Birth-Year Cohort
Multiple sclerosis (MS) is a chronic immune-mediated neurologic disease in which both environmental exposure and inherited susceptibility contribute to disease development. The article by Loonstra et al., published in Neurology in 2024, addresses a central problem in MS genetics: although more than 200 susceptibility loci and several major histocompatibility complex variants have been linked to MS, the extent to which these variants alter an individual’s lifetime risk has remained uncertain. The study therefore moves beyond the question of whether genetic variants are associated with MS and asks how strongly a polygenic risk score (PRS) stratifies real-world lifetime disease probability.
Study Design: A Population-Based Birth-Year Cohort
The investigators used the Dutch Project Y cohort, an unusually valuable epidemiologic resource because it attempted to identify nearly all persons with MS born in the Netherlands in 1966. This design reduced major sources of bias common in hospital-based cohorts, especially differences in age, calendar period, and disease duration. The study included persons with MS from Project Y and non-MS controls from both Project Y and the Amsterdam Dementia Cohort, with controls born between 1963 and 1969. The close birth-year structure is important because it helps align genetic risk estimation with a realistic population denominator rather than with an artificial case-control sample.
Genomic Approach: Constructing the MS Polygenic Risk Score
The authors calculated PRSs using 215 MS-associated susceptibility variants derived from the largest MS genome-wide association study available to them. Participants were genotyped on the same array, underwent imputation and quality control, and individuals with close familial relationships or non-European ancestry were excluded from downstream analyses. The PRS was constructed as a weighted sum of risk alleles, with weights based on log odds ratios from GWAS summary statistics, and then standardized. This approach reflects the polygenic architecture of MS, in which many variants each contribute modestly but collectively can produce substantial stratification of disease risk.
Principal Finding: Genetic Risk Strongly Stratifies Lifetime MS Risk
The central result is striking: the MS-PRS was significantly associated with MS risk, and lifetime risk differed markedly across PRS strata. Among women in the highest 10% of genetic risk, the estimated lifetime risk of MS was approximately 1 in 92, compared with roughly 1 in 2,779 among women in the lowest 30% of genetic risk. Among men, the corresponding estimates were approximately 1 in 293 in the highest 10% and 1 in 7,900 in the lowest 30%. The chart on page 4 visually emphasizes this separation between the highest and lowest genetic-risk groups across age at onset.
Sex-Specific Interpretation of Risk
The study demonstrates that genetic liability operates within a broader sex-specific risk framework. Women had higher absolute lifetime risks than men across comparable PRS strata, consistent with the known female predominance of MS. However, the relative risk contrast between the highest 10% and lowest 30% PRS groups was broadly comparable between sexes, with reported relative risks of 29.4 in women and 26 in men. Figures 2 and 3, shown on pages 5 and 6, further illustrate that the decile-specific lifetime risk curves remain consistently higher in women while preserving a similar genetic gradient in both sexes.
Disease Course: Risk Genetics Did Not Predict Severity Measures
A clinically important negative finding is that the PRS did not significantly associate with age at MS onset, age at progression, or time to secondary progression after correction for multiple testing. In other words, the genetic architecture captured by this MS susceptibility PRS appears to be more informative for disease occurrence than for disease trajectory. This distinction is biologically meaningful: genes that increase susceptibility to immune-mediated disease initiation may differ from genes that influence neurodegeneration, repair, resilience, or progression after disease onset.
Clinical Implications and Limitations
The authors suggest that PRS may eventually support diagnostic certainty in individuals with suspected MS, particularly because a very low PRS could serve as a warning signal when considering MS mimics. However, the findings should not be interpreted as sufficient for diagnosis or screening in isolation. The cohort was Dutch and restricted to participants of European ancestry, and the authors note that PRS performance may not generalize to non-European populations or other birth cohorts. The study is therefore best understood as an important proof of concept: inherited polygenic liability can strongly stratify lifetime MS risk, but clinical implementation will require ancestry-aware validation, integration with environmental risk factors, and careful evaluation in diagnostic workflows.
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.
