Evaluating multiple sclerosis severity loci 30 years after a clinically isolated syndrome

Area of Science:

• Neurogenetics
• Clinical Neurology
• Longitudinal Studies

Background:

• The rs10191329 locus was previously linked to multiple sclerosis (MS) pathology, including cortical lesions and brain atrophy.
• However, replication studies in observational cohorts like MSBase have not consistently associated this locus with disability outcomes.
• This highlights a need to investigate genetic associations with MS severity in long-term, well-phenotyped cohorts.

Purpose of the Study:

• To evaluate the association of the rs10191329 locus and other MSBase loci with long-term disability and MRI outcomes in a unique cohort.
• To assess genetic contributions to disease severity, course, and neurodegenerative/inflammatory changes over 30 years post-clinically isolated syndrome.

Main Methods:

• A cohort of 53 individuals with clinically isolated syndrome was followed for 30 years.
• Deep clinical phenotyping, including age-related MS severity score and Expanded Disability Status Scale, was performed.
• Brain MRI measures (lesions, atrophy) and genetic data were analyzed using regression and survival analyses.

Main Results:

• The rs10191329 locus showed no association with 30-year MS severity, secondary progressive MS diagnosis, or MRI features.
• MSBase loci were also not associated with 30-year disease severity.
• The locus rs73091975 was significantly associated with a lower 14-year age-related MS severity score in individuals who developed MS.

Conclusions:

• The rs10191329 genetic locus does not appear to predict long-term multiple sclerosis severity or disability outcomes.
• Genetic effects on MS severity may be non-linear and interact dynamically with disease duration, becoming more pronounced in earlier disease stages.
• Further research is needed to understand the complex interplay between genetics and the long-term progression of multiple sclerosis.