Genetics

This blog post examines by Rivier and colleagues that evaluates whether a previously published multiple sclerosis (MS) polygenic risk score (PRS), derived largely from European-ancestry GWAS signals, can stratify MS risk equitably across genetic ancestries using the All of Us Research Program. Leveraging whole-genome sequencing linked to electronic health records, the authors analyzed ancestry-matched samples (32,428 individuals each of European, African, and Latino/admixed American ancestry) and quantified MS associations across PRS quintiles while adjusting for age, sex, and genetic principal components. The PRS demonstrated clear dose–response risk stratification in European and Latino/admixed American groups (with the highest quintile showing materially increased odds relative to the lowest), but showed attenuated, statistically non-significant stratification in the African ancestry group. The findings highlight a central challenge in contemporary statistical genetics: PRS portability is limited when discovery cohorts underrepresent non-European populations, due to differences in linkage disequilibrium structure, allele frequencies, and potentially heterogeneous genetic architectures. The study therefore reinforces the methodological and ethical imperative to expand diverse GWAS discovery efforts and to develop, calibrate, and validate multi-ancestry or ancestry-aware PRS before any downstream translational use in risk enrichment or precision medicine.