Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease
Ventham NT., Kennedy NA., Adams AT., Kalla R., Heath S., O'Leary KR., Drummond H., Lauc G., Campbell H., McGovern DPB., Annese V., Zoldoš V., Permberton IK., Wuhrer M., Kolarich D., Fernandes DL., Theorodorou E., Merrick V., Spencer DI., Gardner RA., Doran R., Shubhakar A., Boyapati R., Rudan I., Lionetti P., Akmačić IT., Krištić J., Vučković F., Štambuk J., Novokmet M., Pučić-Baković M., Gornik O., Andriulli A., Cantoro L., Sturniolo G., Fiorino G., Manetti N., Latiano A., Kohn A., D’Incà R., Danese S., Arnott ID., Noble CL., Lees CW., Shand AG., Ho G-T., Dunlop MG., Murphy L., Gibson J., Evenden L., Wrobel N., Gilchrist T., Fawkes A., Kammeijer GSM., Clerc F., de Haan N., Vojta A., Samaržija I., Markulin D., Klasić M., Dobrinić P., Aulchenko Y., van den Heuve T., Jonkers D., Pierik M., Vatn S., Ricanek P., Jahnsen J., You P., Sølvernes J., Frengen AB., Tannæs TM., Moen AEF., Dahl FA., Lindstrøm JC., Ekeland GS., Detlie TE., Keita ÅV., Söderholm JD., Hjortswang H., Halfvarson J., Bergemalm D., Gomollón F., D'Amato M., Törkvist L., Hjelm F., Gullberg M., Nordberg N., Ocklind A., Pettersson E., Ekman D., Sundell M., Modig E., Veillard A-C., Schoemans R., Poncelet D., Sabatel C., Gut M., Bayes M., Casén C., Lindahl T., Ciemniejewska E., Vatn MH., Wilson DC., Gut IG., Nimmo ER., Satsangi J.
AbstractEpigenetic 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, ITGB2andTXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci;VMP1/microRNA-21methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within theTXKpromoter 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.