Genome-wide discovery of multiple sclerosis genetic risk variant allelic regulatory activity

Multiple Sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) with a complex etiology involving environmental and genetic factors. Numerous genetic risk loci for MS have been nominated through genome-wide association studies, with most associated variants residing in non-coding regions. However, further work is needed to understand how genetic variation contributes to disease-related alterations to gene expression. Here, we use massively parallel reporter assays (MPRAs) to identify genetic risk variants with genotype-dependent enhancing or silencing activity within a set of 14,276 variants distributed among 233 independent multiple sclerosis risk loci that have reached genome-wide or suggestive significance. We applied our MPRA library to a commercially available B cell line (GM12878) as well as B cell lines derived from two patients with MS. In total, our approach discovered 150 allelic enhancer variants and 286 allelic silencing variants, representing 83 independent MS risk loci. Collectively, our systematic, genome-scale approach implicates causal genotype-dependent gene regulatory mechanisms for 38% of the known or suggestive MS risk loci, providing a unique resource for the discovery of the genetic mechanisms underlying this chronic inflammatory disease.