Multiple sclerosis genetics and vitamin D-regulated genes involved in cognitive functions.

Background: Cognitive impairment (CI) is a symptom affecting 40-70% of patients with multiple sclerosis (MS). Both MS and CI are associated with vitamin D deficiency. Objective: To identify genetic risk loci and vitamin D-regulated genes involved in cognitive functions. Methods: Identification of shared risk loci between MS, white matter microstructure (WMM) and cognitive performance/ability/intelligence (Cog/Intell) from the Catalogue of Genome-Wide Association Studies (GWAS). Co-localisation analysis between 1alpha,25-Dihydroxyvitamin D3 (1,25D) regulated genes from RNA sequencing and risk loci. Semi-quantitative Western blots of 1,25D-protein regulation. Results: We identified 6 risk loci shared between MS and Cog/Intell, probably corresponding to MPHOSPH9, FOXP1, TET2, ZNHIT3, MEF2C and ATXN1 genes; and two between MS and White Matter Microstructure, ATXN2 and PLEC genes, implicated in neuropsychological diseases. In addition, we found 22 1,25D-regulated genes colocalised with MS risk loci and 47 with Cog/Intell, none in common. Of the latter, the proteins EFL1 and NPC1, which function in ribosome biogenesis and intracellular cholesterol trafficking, respectively, were highly regulated by 1,25D and have also been associated with neurodegeneration and CI. Conclusions: CI may be promoted by MS genetics, but also by MS-independent genes regulated by 1,25D. These specific interactions could be useful against MS and CI.