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Updated: Oct 25, 2025
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
White matter microstructural differences in children and genetic risk for multiple sclerosis: A population-based
C Louk de Mol1, Rinze F Neuteboom2, Philip R Jansen3
1Department of Neurology, MS Center ErasMS, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands/The Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
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.
Insights
Genetic risk for multiple sclerosis (MS) is linked to distinct white matter microstructural changes in children. This study reveals how genetic predisposition relates to brain development patterns in youth.
Area of Science:
- Neuroimaging
- Pediatric Neurology
- Genetics
Background:
- Multiple sclerosis (MS) patients exhibit white matter (WM) abnormalities on brain imaging, with varied lesion locations.
- The "pothole" method analyzes diffusion-weighted images to identify distinct clusters of altered WM microstructure.
Purpose of the Study:
- To examine the association between genetic risk for MS and independent clusters of decreased or increased fractional anisotropy (FA) in the brain.
- To investigate sex- and age-related differences in these patterns.
Main Methods:
- Diffusion tensor imaging (DTI) data were collected from 3047 children aged 8-12.
- Quantified "potholes" (low FA clusters) and "molehills" (high FA clusters) globally and by tract.
- Assessed the relationship between a polygenic risk score (PRS) for MS and the number of potholes/molehills using linear regression, correcting for multiple testing.
Main Results:
- The number of molehills increased with age, while potholes decreased with age.
- Fewer potholes were observed in girls during typical development.
- A positive association was found between the MS polygenic risk score (PRS) and the number of molehills (β = 0.9, p = 0.002). Molehills were more prevalent in the corpus callosum.
Conclusions:
- Genetic risk for MS is associated with distinct clusters of increased FA in the developing brain during childhood.
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