Environmental multiple sclerosis (MS) risk factors, genetic MS risk, and brain development in a general paediatric population

Background Neuroaxonal loss occurs in the early stages of multiple sclerosis (MS), but whether it results from early inflammatory brain damage or an ongoing neurodegenerative process remains unclear. We hypothesise that genetic and childhood environmental risk factors for MS may already have an impact on neurodevelopment before the typical age of onset for MS in the general population. Methods We examined associations and interactions of genetic and environmental risk factors for MS with brain MRI outcomes, including volumetric (n=5350) and diffusion data (n=5649), at ages 9 and 13 years in a large, population-based childhood cohort without MS diagnoses. Polygenic risk scores (PRSs) were used to assess genetic burden, with rs10191329 as a marker of MS severity. Environmental factors at age 5 included Epstein-Barr virus (EBV) serology, vitamin D status, body mass index, duration of outdoor activities, and household parental smoking. Results Genetic data were available for 2817 and 2970 participants with volumetric and diffusion data, respectively. The MS-PRS was positively associated with EBV viral capsid antigen titres among EBV-positive children (β=0.15, p=2.98×10 ⁻⁶). A negative association was observed between the MS-PRS and subcortical grey matter volume (β=−0.03, p=0.014). Interaction between the MS-PRS and household parental smoking was negatively linked to total brain (β=−0.21, p=0.025) and thalamic volumes (β=−0.22, p=0.003), where a higher MS-PRS and household smoking were associated with lower volumes. No associations were observed for rs10191329 with brain outcomes. Conclusions Genetic and environmental risk factors for MS interact to influence brain volumes in childhood, suggesting a potential window for preventing MS in genetically susceptible individuals by reducing exposure to household smoking.