Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease.

Epigenetic alterations may provide important insights into gene-environment interaction in
inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation
differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439
differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs),
which we study in detail using whole genome bisulphite sequencing. We replicate the top
DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using
paired genetic and epigenetic data, we delineate methylation quantitative trait loci;
VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium
with a known IBD susceptibility variant. Separated cell data shows that IBD-associated
hypermethylation within the TXK promoter region negatively correlates with gene expression
in whole-blood and CD8 þ T cells, but not other cell types. Thus, site-specific DNA
methylation changes in IBD relate to underlying genotype and associate with cell-specific
alteration in gene expression.