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

Author:

de Mol C Louk1ORCID,Neuteboom Rinze F2,Jansen Philip R3,White Tonya4

Affiliation:

1. Department 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

2. Department of Neurology, MS Center ErasMS, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

3. The Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands/Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands/Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

4. Department of Child and Adolescent Psychiatry, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

Abstract

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.

Funder

Stichting MS Research

ZonMw

Publisher

SAGE Publications

Subject

Neurology (clinical),Neurology

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