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

Multiple sclerosis is an immune-mediated demyelinating disease of the central nervous system with a complex etiology involving environmental and genetic factors. Numerous genetic risk loci for multiple sclerosis have been nominated through genome-wide association studies, with most associated variants residing in noncoding 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 to identify genetic risk variants with genotype-dependent enhancing or silencing activity within a set of 14,275 variants distributed among multiple sclerosis risk loci that have reached genome-wide or suggestive significance. We applied our Massively Parallel Reporter Assay library to Epstein-Barr-virus-transformed B cell lines derived from two patients with multiple sclerosis, 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 multiple sclerosis risk loci. Our systematic, genome-scale approach implicates potentially causal genotype-dependent gene regulatory mechanisms for over a third of the known multiple sclerosis risk loci, providing a unique resource for the discovery of the genetic mechanisms underlying this chronic inflammatory disease.