Polygenic Multiple Sclerosis Risk
The Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
Polygenic Multiple Sclerosis Risk and Population-Based Childhood Brain Imaging
Objective: Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune-mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear. In this study, we explore the association between MS polygenic risk scores (PRS) and brain imaging outcomes from a large, population-based pediatric sample to gain insight into the underlying neurobiology of MS.
Methods: We included 8-to-12 year-old genotyped participants from the Generation R Study in whom T1 -weighted volumetric-(n=1,136) and/or diffusion tensor imaging (n=1,088) had been collected. PRS for MS were calculated based on a large genome-wide association study of MS (n=41,505), and were regressed on regional volumes, global and tract-specific fractional anisotropy (FA) and global mean diffusivity using linear regression.
Results: No associations were observed for the regional volumes. We observed a positive association between the MS-PRS and global FA(β=0.098, standard error (SE)=0.030, p=1.08×10-3 ). Tract-specific analyses showed higher FA and lower radial diffusivity in several tracts. We replicated our findings in an independent sample of children (n=186) who were scanned in an earlier phase (Global FA; β=0.189, SE=0.072, p=9.40×10-3 ).
Interpretation: This is the first study to show that greater genetic predisposition for MS is associated with higher global brain WM FA at an early age in the general population. Our results suggest a pre-adolescent time-window within neurodevelopment in which MS risk variants act upon the brain. This article is protected by copyright. All rights reserved.