Genetics

This article presents a multimodal multiple sclerosis (MS) risk scoring framework designed to stratify asymptomatic individuals—particularly unaffected siblings of people with MS—by integrating established genetic susceptibility markers and environmental/clinical risk factors into a single additive score. Using genotyping (including HLA-DRB1*1501 and GWAS-identified SNPs) alongside serological and exposure measures such as anti–EBNA-1 IgG titre, smoking history, and infectious mononucleosis, the authors demonstrate that unaffected siblings exhibit intermediate risk distributions between MS cases and unrelated controls, with a best-performing model achieving an AUC of 0.82 for case–control discrimination. While targeted MRI and spectroscopy in high- versus low-score siblings did not show clear separations in subclinical CNS pathology, the findings support the score’s potential utility as a scalable screening tool to enrich pre-symptomatic cohorts for longitudinal surveillance and future prevention-oriented trials, pending prospective validation.