A Systems Biology approach to determine cell-specific gene regulatory effects of genetic associations in multiple sclerosis

We have conducted a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS); which analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our approach makes extensive use of gene regulatory data generated by the ENCODE and REP projects to build data-driven models of the predicted regulatory effects (PRE) of each associated variant and their flanking correlated variation over a wide range of linkage disequilibrium thresholds.

The detailed mapping of regulatory information for each SNP suggests that if PRE are computed for a given cell type in a single individual based on the carriage of relevant risk alleles, these values should capture a non-negligible proportion of the variance in gene expression in that cell type. To test this hypothesis, we interrogated the expression of the entire transcriptome of FACS-sorted CD4+ T cells, and CD14+ monocytes from 25 MS patients by RNAseq and then assessed the co...