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 correlation of their genotype dependent PRE and their actual
gene expression in each cell type separately. Our results showed that the
correlation observed was in all cases significantly higher than what would
be expected by chance if these metrics were independent. Furthermore, the
computed correlations were always higher for the matching cell type
(CD4/CD8 expression with T cells PRE and CD14 expression with monocytes
PRE).  The average correlation between RNA expression and PRE
within the same cell type was 0.331 (CD4 vs. T
cells, p<10-300), 0.324 (CD8 vs. T
cells, p<10-300), and 0.246 (CD14 vs.
monocytes, p<10-300), representing a significantly higher
than expected value for each cell type. Correlations between PRE and RNA
expression of mismatched cell types were significantly lower. These
results suggest that the computation of PRE can be applied to single
patients and individual scores can be generated for each of them.