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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 preadolescent time window within neurodevelopment in which MS risk variants act upon the brain.  ANN NEUROL 2020;87:774–787

Polygenic Multiple Sclerosis Risk and Population‐Based Childhood Brain Imaging