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

Ventham, N. T.; Kennedy, N. A.; Adams, A. T.; Kalla, Rahul; Heath, Simon; O'Leary, K. R.; Drummond, H.; IBD BIOM consortium; IBD CHARACTER consortium; Wilson, D. C.; Gut, Ivo Glynne; Nimmo, E. R.; Satsangi, Jack

doi:http://dx.doi.org/10.1038/ncomms13507

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

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Ventham NT, Kennedy NA, Adams AT, Kalla R, Heath S, O'Leary KR, Drummond H, IBD BIOM consortium, IBD CHARACTER consortium, Wilson DC, Gut IG, Nimmo ER, Satsangi J. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. Nature Communications. 2016; 7: 13507. DOI: 10.1038/ncomms13507

Abstract

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+ 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.