Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease
Nicholas T. Ventham(Edinburgh Genomics), Nicholas A. Kennedy(Edinburgh Genomics), Alex Adams(Edinburgh Genomics), Rahul Kalla(Edinburgh Genomics), Simon Heath(Universitat Pompeu Fabra), Katherine O'Leary(Edinburgh Genomics), HE Drummond(Edinburgh Genomics), Gordan Lauc(Genos (Croatia)), Harry Campbell(University of Edinburgh), Dermot McGovern(Cedars-Sinai Medical Center), Vito Annese(Azienda Ospedaliero-Universitaria Careggi), Vlatka Zoldoš(University of Zagreb), Iain K. Permberton, Manfred Wuhrer(Leiden University Medical Center), Daniel Kolarich(Max Planck Institute of Colloids and Interfaces), Daryl L. Fernandes(Culham Science Centre), Evropi Theorodorou(University of Edinburgh), Victoria Merrick(University of Edinburgh), Daniel I. R. Spencer(Culham Science Centre), Richard A. Gardner(Culham Science Centre), Ray Doran(Culham Science Centre), Archana Shubhakar(Culham Science Centre), Ray Boyapati(University of Edinburgh), Igor Rudan(University of Edinburgh), Paolo Lionetti(Meyer Children's Hospital), Irena Trbojević‐Akmačić(Genos (Croatia)), Jasminka Krištić(Genos (Croatia)), Frano Vučković(Genos (Croatia)), Jerko Štambuk(Genos (Croatia)), Mislav Novokmet(Genos (Croatia)), Maja Pučić‐Baković(Genos (Croatia)), Olga Gornik(University of Zagreb), Angelo Andriulli(Istituti di Ricovero e Cura a Carattere Scientifico), Laura Cantoro(IRCCS San Camillo Hospital), G.C. Sturniolo(University of Padua), Gionata Fiorino, Natalia Manetti(Azienda Ospedaliero-Universitaria Careggi), Anna Latiano(Istituti di Ricovero e Cura a Carattere Scientifico), Anna Kohn(IRCCS San Camillo Hospital), R. D’Incà(University of Padua), Silvio Danese, Ian Arnott(Western General Hospital), Colin Noble(Western General Hospital), Charlie W. Lees(Western General Hospital), Alan G. Shand(Western General Hospital), Gwo‐Tzer Ho(Western General Hospital), Malcolm G. Dunlop(Institute of Genetics and Cancer), Lee Murphy(Western General Hospital), Jude Gibson(Western General Hospital), Louise Evenden(Western General Hospital), Nicola Wrobel(Western General Hospital), T. L. Gilchrist(Western General Hospital), Angie Fawkes(Western General Hospital), Guinevere S. M. Lageveen‐Kammeijer(Leiden University Medical Center), Florent Clerc(Leiden University Medical Center), Noortje de Haan(Leiden University Medical Center), Aleksandar Vojta(University of Zagreb), Ivana Samaržija(University of Zagreb), Dora Markulin(University of Zagreb), Marija Klasić(University of Zagreb), Paula Dobrinić(University of Zagreb), Yurii S. Aulchenko(Institute of Cytology and Genetics), Tim van den Heuve(Maastricht University Medical Centre), Daisy Jonkers(Maastricht University Medical Centre), Marieke Pierik(Maastricht University Medical Centre), Simen Vatn(Akershus University Hospital), Petr Ricanek(Akershus University Hospital), Jørgen Jahnsen(Akershus University Hospital), Panpan You(Akershus University Hospital), Janne Sølvernes(Akershus University Hospital), Anna B. Frengen(Oslo University Hospital), Tone M Tannæs(Oslo University Hospital), Aina Elisabeth Fossum Moen(Oslo University Hospital), Fredrik A. Dahl(Oslo University Hospital), Jonas Christoffer Lindstrøm(Oslo University Hospital), Gunn S. Ekeland(Oslo University Hospital), Trond Espen Detlie(Oslo University Hospital), Åsa V. Keita(Linköping University Hospital), Johan D. Söderholm(Linköping University Hospital), Henrik Hjortswang(Örebro County Council), Jonas Halfvarson(Örebro University), Daniel Bergemalm(Örebro University), Fernando Gomollón(Universidad de Zaragoza), Mauro D’Amato(BioCruces Health research Institute), Leif Törkvist(Karolinska Institutet), Fredrik Hjelm(Olink Bioscience (Sweden)), Mats Gullberg(Olink Bioscience (Sweden)), Niklas Nordberg(Olink Bioscience (Sweden)), Anette Ocklind(Olink Bioscience (Sweden)), Erik Pettersson(Olink Bioscience (Sweden)), Daniel Ekman(Olink Bioscience (Sweden)), Mikael Sundell(Olink Bioscience (Sweden)), Eddie Modig(Olink Bioscience (Sweden)), Anne-Clémence Veillard(Diagenode (Belgium)), Renaud Schoemans(Diagenode (Belgium)), Dominique Poncelet(Diagenode (Belgium)), Céline Sabatel(Diagenode (Belgium)), Marta Gut(Universitat Pompeu Fabra), Mónica Bayés(Universitat Pompeu Fabra), Christina Casèn(Genetic Analysis (Norway)), Torbjørn Lindahl(Genetic Analysis (Norway)), Ewa Ciemniejewska(Genetic Analysis (Norway)), Morten H. Vatn(Oslo University Hospital), Desiree Wilson(University of Edinburgh), Marta Gut(Universitat Pompeu Fabra), Elaine R. Nimmo(Edinburgh Genomics), Jack Satsangi(Edinburgh Genomics)
Cited by 273Open Access
Abstract
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.