Differential results of genetic risk scoring for multiple sclerosis in European and African American populations

Background: Genetic risk scores (GRSs) for multiple sclerosis (MS) help identify high-risk individuals and stratify populations for clinical trials, but most are derived from European populations, raising questions about GRS accuracy in other ancestries. Objectives: We aimed to determine whether an MS GRS can stratify individuals of African and Latino/admixed ancestry and assess whether the JointPRS tool enhances GRS portability in African ancestry. Methods: In this cross-sectional study using All of Us (2018–2022), we derived a GRS from 232 variants for 32,428 European, 32,428 African, and 32,428 Latino/admixed participants, each divided into quintiles. The outcome was MS ascertained through International Classification of Diseases (ICD)-9/10 and Systematized Nomenclature of Medicine (SNOMED) codes. JointPRS was used to improve GRS portability in the African-ancestry group. Results: MS prevalence was 1.0% in European, 0.56% in African, and 0.46% in Latino/admixed participants. The GRS stratified MS risk effectively in European (odds ratio (OR) = 2.30 (1.60–3.36); p -trend < 0.001) and Latino/admixed (OR = 2.53 (1.43–4.85); p -trend < 0.001) ancestry groups but did not significantly partition African participants (OR = 1.30 (0.88–1.95); p -trend = 0.17). After applying JointPRS, stratification in African ancestry improved (OR = 3.02 (1.00–8.95); p -trend = 0.007). Discussion: A GRS for MS stratified European and Latino/admixed individuals but not African ancestry. Incorporating African-specific data enhanced performance, underscoring the need for more ancestry-tailored GRS.