Associating a Polygenic Risk Score for Multiple Sclerosis with Brain MRI Metrics and Cognitive Performance in Healthy UK Biobank Participants.

PURPOSE: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system influenced by both genetic and environmental factors. Although a polygenic risk score for MS (MS-PRS) is associated with disease susceptibility, its relationship with white matter (WM) microstructure and cognition in neurologically healthy individuals remains unclear. This study investigated associations of MS-PRS with diffusion MRI metrics and cognitive function in healthy individuals.

METHODS

This cross-sectional study included 35952 neurologically healthy UK Biobank participants with available MS-PRS, diffusion MRI, and cognitive data. Associations between MS-PRS and 11 cognitive measures were tested using generalized linear models adjusted for age, age squared, sex, genetic principal components, body mass index, and intracranial volume, with false discovery rate (FDR) correction. Participants were then stratified by MS-PRS quartiles. For cognitive measures showing significant associations in the highest MS-PRS group, follow-up analyses evaluated associations between MS-PRS and diffusion MRI metrics in WM regions previously associated with reaction time (RT). Mediation analysis was then performed.

RESULTS

In the full sample, MS-PRS was not significantly associated with any cognitive measure after multiple-comparison correction. In the highest MS-PRS group, the higher MS-PRS was significantly associated with longer RT (β = 0.048, FDR-corrected P = 0.047). In the highest MS-PRS group, the higher MS-PRS was associated with higher mean diffusivity (MD) in the splenium of the corpus callosum (CC) (β = 0.021, FDR-corrected P = 0.024). MD in the splenium of the CC showed a small partial mediation effect on the association between MS-PRS and RT in the highest MS-PRS group (mediation effect 3.0%).

CONCLUSION

In neurologically healthy individuals, a higher genetic burden for MS was associated with slower information processing speed in the highest-risk subgroup and with altered WM microstructure in the splenium of the CC. These findings suggest that subtle WM differences may partly underlie the association between MS genetic susceptibility and cognitive performance.