Differential Results of Polygenic Risk Scoring for Multiple Sclerosis in European and African American Populations

Abstract Importance The risk of multiple sclerosis (MS) is significantly influenced by polygenic inheritance. Polygenic risk scores (PRS) for MS can help identify high-risk individuals and stratify populations for clinical trials. However, most genome-wide association studies (GWAS) have been conducted in populations of European ancestry, raising questions about the accuracy of these PRS in other ancestries. Objective To determine whether a PRS for MS can effectively stratify individuals of non-European ancestries. Design, setting and participants This cross-sectional study utilized prospectively collected data from the All of Us Research Program (2018-2023). It included participants who had both whole genome sequencing and electronic health record (EHR) data. Exposure(s) A PRS comprising 282 independent single nucleotide variants for MS, divided into quintiles. Main Outcome(s) and Measure(s) Prevalence of multiple sclerosis ascertained through ICD-10 or SNOMED codes. Results In this study population, MS cases comprised 1.0% (327 cases) of the European population, 0.56% (183 cases) of the African population, and 0.46% (150 cases) of the Latino/admixed American population. In analyses adjusting for age, sex, and genetic principal components, the PRS associates with MS risk in the European population, with a 141% increase in the risk of MS for individuals in the highest compared to the lowest PRS quintile (OR: 2.41 [1.69-3.50], test-for-trend p<0.001). Similarly, the PRS appropriately partitions the Latino/admixed population into increasing MS risk groups (OR: 2.56 [1.45-4.78], test-for-trend p-value <0.001). However, it did not significantly stratify the African population into distinct MS risk categories (OR: 1.45 [0.95-2.25], test-for-trend p=0.10). Conclusions and Relevance A PRS for MS effectively stratified individuals of European and Latino/admixed ancestries but not African ancestry. This highlights the need for ancestry-specific PRS development to ensure accurate risk prediction across diverse populations, emphasizing the importance of including non-European groups in MS genetic research.