@article{55ae0096a9be46618cdefe626ebc33c1,
title = "Polygenic Multiple Sclerosis Risk and Population-Based Childhood Brain Imaging",
abstract = "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.",
author = "{de Mol}, {C. Louk} and Jansen, {Philip R.} and Muetzel, {Ryan L.} and Knol, {Maria J.} and Adams, {Hieab H.} and Jaddoe, {Vincent W.} and Vernooij, {Meike W.} and Hintzen, {Rogier Q.} and White, {Tonya J.} and Neuteboom, {Rinze F.}",
note = "Funding Information: This study was supported by the Dutch Multiple Sclerosis Research Foundation. Neuroimaging was supported by Netherlands Organization for Health Research and Development (ZonMw) TOP project 91211021. Supercomputing computations were supported by the Netherlands Organisation for Scientific Research (NOW) Physical Sciences Division (Exacte Wetenschappen) and SURFsara (Cartesius compute cluster, www.surfsara.nl ). The Generation R Study has been conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR‐MDC). The general design of the Generation R Study was made possible by financial support from the Erasmus Medical Center, the Erasmus University Rotterdam, the ZonMw, the NOW, and the Ministry of Health, Welfare, and Sport. Funding Information: This study was supported by the Dutch Multiple Sclerosis Research Foundation. Neuroimaging was supported by Netherlands Organization for Health Research and Development (ZonMw) TOP project 91211021. Supercomputing computations were supported by the Netherlands Organisation for Scientific Research (NOW) Physical Sciences Division (Exacte Wetenschappen) and SURFsara (Cartesius compute cluster, www.surfsara.nl). The Generation R Study has been conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC). The general design of the Generation R Study was made possible by financial support from the Erasmus Medical Center, the Erasmus University Rotterdam, the ZonMw, the NOW, and the Ministry of Health, Welfare, and Sport. We thank the International Multiple Sclerosis Genetics Consortium for providing us with data from their genome-wide association studies, which were used to calculate the polygenic risk scores for this study. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam for their participation in the Generation R study. Publisher Copyright: {\textcopyright} 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.",
year = "2020",
month = may,
day = "1",
doi = "10.1002/ana.25717",
language = "English",
volume = "87",
pages = "774--787",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley & Sons Inc.",
number = "5",
}