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 14,275 variants distributed among MS risk loci that have reached genome-wide or suggestive significance. We applied our MPRA library to EBV-transformed B cell lines derived from two patients with MS, as well as the ENCODE Tier 1 cell line GM12878. In total, our approach discovered 150 allelic enhancing variants and 286 allelic silencing variants, collectively representing 83 independent MS risk loci. Our systematic, genome-scale approach implicates potentially causal genotype-dependent gene regulatory mechanisms for over a third of the known MS risk loci, providing a unique resource for the discovery of the genetic mechanisms underlying this chronic inflammatory disease.