Relevance of Multiple Sclerosis Severity Genotype in Predicting Disease Course: A Real-World Cohort

Objective: Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome-wide association studies recently found the first genome-wide significant single-nucleotide variant (SNV; rs10191329 ) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management.

Methods: We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well-characterized prospective cohort of 1,455 MS patients. We used logistic regression, survival analysis, and propensity score matching to predict relevant long-term clinical outcomes.

Results: We were unable to detect any association between rs10191329 and a range of clinically relevant outcomes (eg, time to Expanded Disability Status Scale milestones, age-related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case-control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329 . However, we were able to replicate the association of two suggestive SNVs (rs7289446 and rs868824 ) with the development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset.

Interpretation: Identification of rs10191329 and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome-wide association studies associated with disease progression in neurodegenerative disorders. ANN NEUROL 2024;95:459-470.