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

N. T. Ventham; N. A. Kennedy; A. T. Adams; R. Kalla; S. Heath; K. R. O'Leary; H. Drummond; D. C. Wilson; I. G. Gut; E. R. Nimmo; J. Satsangi; IBD BIOM consortium; IBD CHARACTER consortium

doi:10.1038/ncomms13507

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

N. T. Ventham, N. A. Kennedy, A. T. Adams, R. Kalla, S. Heath, K. R. O'Leary, H. Drummond, D. C. Wilson, I. G. Gut, E. R. Nimmo, J. Satsangi, IBD BIOM consortium, IBD CHARACTER consortium

Research output: Contribution to journal › Article › Research › peer-review

211 Citations (Scopus)

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.

Original language	English
Article number	13507
Number of pages	14
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13507
Publication status	Published - 25 Nov 2016
Externally published	Yes

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Ventham, N. T., Kennedy, N. A., Adams, A. T., Kalla, R., Heath, S., O'Leary, K. R., Drummond, H., Wilson, D. C., Gut, I. G., Nimmo, E. R., Satsangi, J., IBD BIOM consortium, & IBD CHARACTER consortium (2016). Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. Nature Communications, 7, Article 13507. https://doi.org/10.1038/ncomms13507

@article{ab9887e64f1c43128f0f3fd562cb254a,

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

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.",

author = "Ventham, \{N. T.\} and Kennedy, \{N. A.\} and Adams, \{A. T.\} and R. Kalla and S. Heath and O'Leary, \{K. R.\} and H. Drummond and Wilson, \{D. C.\} and Gut, \{I. G.\} and Nimmo, \{E. R.\} and J. Satsangi and \{IBD BIOM consortium\} and Gordan Lauc and Harry Campbell and McGovern, \{Dermot P.B.\} and Vito Annese and Vlatka Zoldo{\v s} and Permberton, \{Iain K.\} and Manfred Wuhrer and Daniel Kolarich and Fernandes, \{Daryl L.\} and Evropi Theorodorou and Victoria Merrick and Spencer, \{Daniel I.\} and Gardner, \{Richard A.\} and Ray Doran and Archana Shubhakar and Ray Boyapati and Igor Rudan and Paolo Lionetti and Akma{\v c}i{\'c}, \{Irena Trbojevi{\'c}\} and Jasminka Kri{\v s}ti{\'c} and Frano Vu{\v c}kovi{\'c} and Jerko {\v S}tambuk and Mislav Novokmet and Maja Pu{\v c}i{\'c}-Bakovi{\'c} and Olga Gornik and Angelo Andriulli and Laura Cantoro and Giancarlo Sturniolo and Gionata Fiorino and Natalia Manetti and Anna Latiano and Anna Kohn and Renata D'Inc{\`a} and Silvio Danese and Arnott, \{Ian D.\} and Noble, \{Colin L.\} and Lees, \{Charlie W.\} and Shand, \{Alan G.\} and Ho, \{Gwo Tzer\} and Dunlop, \{Malcolm G.\} and Lee Murphy and Jude Gibson and Louise Evenden and Nicola Wrobel and Tamara Gilchrist and Angie Fawkes and Kammeijer, \{Guinevere S.M.\} and Florent Clerc and \{De Haan\}, Noortje and Aleksandar Vojta and Ivana Samar{\v z}ija and Dora Markulin and Marija Klasi{\'c} and Paula Dobrini{\'c} and Yurii Aulchenko and \{Van Den Heuve\}, Tim and Daisy Jonkers and Marieke Pierik and \{IBD CHARACTER consortium\} and Simen Vatn and Petr Ricanek and J{\o}rgen Jahnsen and Panpan You and Janne S{\o}lvernes and Frengen, \{Anna B.\} and Tann{\ae}s, \{Tone M.\} and Moen, \{Aina E.F.\} and Dahl, \{Fredrik A.\} and Lindstr{\o}m, \{Jonas Christoffer\} and Ekeland, \{Gunn S.\} and Detlie, \{Trond Espen\} and Keita, \{{\AA}sa V.\} and S{\"o}derholm, \{Johan D.\} and Henrik Hjortswang and Jonas Halfvarson and Daniel Bergemalm and Fernando Gomoll{\'o}n and Mauro D'Amato and Leif T{\"o}rkvist and Fredrik Hjelm and Mats Gullberg and Niklas Nordberg and Anette Ocklind and Erik Pettersson and Daniel Ekman and Mikael Sundell and Eddie Modig and Veillard, \{Anne Cl{\'e}mence\} and Renaud Schoemans and Dominique Poncelet and C{\'e}line Sabatel and Marta Gut and Monica Bayes and Christina Cas{\'e}n and Torbj{\o}rn Lindahl and Ewa Ciemniejewska and Vatn, \{Morten H.\}",

year = "2016",

month = nov,

day = "25",

doi = "10.1038/ncomms13507",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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

TY - JOUR

T1 - Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

AU - Ventham, N. T.

AU - Kennedy, N. A.

AU - Adams, A. T.

AU - Kalla, R.

AU - Heath, S.

AU - O'Leary, K. R.

AU - Drummond, H.

AU - Wilson, D. C.

AU - Gut, I. G.

AU - Nimmo, E. R.

AU - Satsangi, J.

AU - IBD BIOM consortium

AU - Lauc, Gordan

AU - Campbell, Harry

AU - McGovern, Dermot P.B.

AU - Annese, Vito

AU - Zoldoš, Vlatka

AU - Permberton, Iain K.

AU - Wuhrer, Manfred

AU - Kolarich, Daniel

AU - Fernandes, Daryl L.

AU - Theorodorou, Evropi

AU - Merrick, Victoria

AU - Spencer, Daniel I.

AU - Gardner, Richard A.

AU - Doran, Ray

AU - Shubhakar, Archana

AU - Boyapati, Ray

AU - Rudan, Igor

AU - Lionetti, Paolo

AU - Akmačić, Irena Trbojević

AU - Krištić, Jasminka

AU - Vučković, Frano

AU - Štambuk, Jerko

AU - Novokmet, Mislav

AU - Pučić-Baković, Maja

AU - Gornik, Olga

AU - Andriulli, Angelo

AU - Cantoro, Laura

AU - Sturniolo, Giancarlo

AU - Fiorino, Gionata

AU - Manetti, Natalia

AU - Latiano, Anna

AU - Kohn, Anna

AU - D'Incà, Renata

AU - Danese, Silvio

AU - Arnott, Ian D.

AU - Noble, Colin L.

AU - Lees, Charlie W.

AU - Shand, Alan G.

AU - Ho, Gwo Tzer

AU - Dunlop, Malcolm G.

AU - Murphy, Lee

AU - Gibson, Jude

AU - Evenden, Louise

AU - Wrobel, Nicola

AU - Gilchrist, Tamara

AU - Fawkes, Angie

AU - Kammeijer, Guinevere S.M.

AU - Clerc, Florent

AU - De Haan, Noortje

AU - Vojta, Aleksandar

AU - Samaržija, Ivana

AU - Markulin, Dora

AU - Klasić, Marija

AU - Dobrinić, Paula

AU - Aulchenko, Yurii

AU - Van Den Heuve, Tim

AU - Jonkers, Daisy

AU - Pierik, Marieke

AU - IBD CHARACTER consortium

AU - Vatn, Simen

AU - Ricanek, Petr

AU - Jahnsen, Jørgen

AU - You, Panpan

AU - Sølvernes, Janne

AU - Frengen, Anna B.

AU - Tannæs, Tone M.

AU - Moen, Aina E.F.

AU - Dahl, Fredrik A.

AU - Lindstrøm, Jonas Christoffer

AU - Ekeland, Gunn S.

AU - Detlie, Trond Espen

AU - Keita, Åsa V.

AU - Söderholm, Johan D.

AU - Hjortswang, Henrik

AU - Halfvarson, Jonas

AU - Bergemalm, Daniel

AU - Gomollón, Fernando

AU - D'Amato, Mauro

AU - Törkvist, Leif

AU - Hjelm, Fredrik

AU - Gullberg, Mats

AU - Nordberg, Niklas

AU - Ocklind, Anette

AU - Pettersson, Erik

AU - Ekman, Daniel

AU - Sundell, Mikael

AU - Modig, Eddie

AU - Veillard, Anne Clémence

AU - Schoemans, Renaud

AU - Poncelet, Dominique

AU - Sabatel, Céline

AU - Gut, Marta

AU - Bayes, Monica

AU - Casén, Christina

AU - Lindahl, Torbjørn

AU - Ciemniejewska, Ewa

AU - Vatn, Morten H.

PY - 2016/11/25

Y1 - 2016/11/25

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms13507

DO - 10.1038/ncomms13507

M3 - Article

C2 - 27886173

AN - SCOPUS:84998610927

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 13507

ER -

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

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