Genetics

This blog post critically examines the study by Loonstra and colleagues investigating how a multiple sclerosis (MS) polygenic risk score (PRS) can be translated from relative genetic susceptibility into interpretable lifetime absolute risk in a near-complete national birth-year cohort from the Netherlands. It explains the cohort design, genotyping and PRS construction, and the decile-based simulation framework used to map PRS strata onto sex-specific lifetime risk estimates. The post highlights the study’s key finding that individuals in the extreme PRS tails—particularly women—exhibit large gradients in absolute lifetime MS risk, while the same PRS does not meaningfully predict age at onset or progression to secondary progressive disease. Finally, it discusses clinical implications for diagnostic support and misdiagnosis reduction, alongside important limitations regarding ancestry portability, cohort specificity, and the distinction between genetic architecture of susceptibility versus disease course.