White matter microstructural differences in children and genetic risk for multiple sclerosis: A population-based study.

BACKGROUND

MS patients show abnormalities in white matter (WM) on brain imaging, with heterogeneity in the location of WM lesions. The "pothole" method can be applied to diffusion-weighted images to identify spatially distinct clusters of divergent brain WM microstructure.

OBJECTIVE

To investigate the association between genetic risk for MS and spatially independent clusters of decreased or increased fractional anisotropy (FA) in the brain. In addition, we studied sex- and age-related differences.

METHODS

3 Tesla diffusion tensor imaging (DTI) data were collected in 8- to 12-year-old children from a population-based study. Global and tract-based potholes (lower FA clusters) and molehills (higher FA clusters) were quantified in 3047 participants with usable DTI data. A polygenic risk score (PRS) for MS was calculated in genotyped individuals (n = 1087) and linear regression analyses assessed the relationship between the PRS and the number of potholes and molehills, correcting for multiple testing using the False Discovery Rate.

RESULTS

The number of molehills increased with age, potholes decreased with age, and fewer potholes were observed in girls during typical development. The MS-PRS was positively associated with the number of molehills (β = 0.9, SE = 0.29, p = 0.002). Molehills were found more often in the corpus callosum (β = 0.3, SE = 0.09, p = 0.0003).

CONCLUSION

Genetic risk for MS is associated with spatially distinct clusters of increased FA during childhood brain development.