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.

The authors have declared no competing interest.

This study did not receive any funding

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Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The All of Us institutional review board approved the study protocol for this study.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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