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; Gordan Lauc; Harry Campbell; Dermot P.B. McGovern; Vito Annese; Vlatka Zoldoš; Iain K. Permberton; Manfred Wuhrer; Daniel Kolarich; Daryl L. Fernandes; Evropi Theorodorou; Victoria Merrick; Daniel I. Spencer; Richard A. Gardner; Ray Doran; Archana Shubhakar; Ray Boyapati; Igor Rudan; Paolo Lionetti; Irena Trbojevic Akmacic; Jasminka Krištic; Frano Vuckovic; Jerko Štambuk; Mislav Novokmet; Maja Pucic-Bakovic; Olga Gornik; Angelo Andriulli; Laura Cantoro; Giancarlo Sturniolo; Gionata Fiorino; Natalia Manetti; Anna Latiano; Anna Kohn; Renata D'Incà; Silvio Danese; Ian D. Arnott; Colin L. Noble; Charlie W. Lees; Tim van den Heuvel; Daisy Jonkers; Marieke Pierik; 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
, Gordan Lauc
, Harry Campbell
, Dermot P.B. McGovern
, Vito Annese
, Vlatka Zoldoš
, Iain K. Permberton
, Manfred Wuhrer
, Daniel Kolarich
, Daryl L. Fernandes

Evropi Theorodorou, Victoria Merrick, Daniel I. Spencer, Richard A. Gardner, Ray Doran, Archana Shubhakar, Ray Boyapati, Igor Rudan, Paolo Lionetti, Irena Trbojevic Akmacic, Jasminka Krištic, Frano Vuckovic, Jerko Štambuk, Mislav Novokmet, Maja Pucic-Bakovic, Olga Gornik, Angelo Andriulli, Laura Cantoro, Giancarlo Sturniolo, Gionata Fiorino, Natalia Manetti, Anna Latiano, Anna Kohn, Renata D'Incà, Silvio Danese, Ian D. Arnott, Colin L. Noble, Charlie W. Lees, Tim van den Heuvel, Daisy Jonkers, Marieke Pierik, IBD BIOM consortium, IBD Character Consortium

^*Corresponding author for this work

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

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
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13507
Publication status	Published - 25 Nov 2016

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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., Lauc, G., Campbell, H., McGovern, D. P. B., Annese, V., Zoldoš, V., Permberton, I. K., Wuhrer, M., Kolarich, D., ... 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{89021310423f4b12816ee72aa400b8d2,

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 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 Akmacic, \{Irena Trbojevic\} and Jasminka Kri{\v s}tic and Frano Vuckovic and Jerko {\v S}tambuk and Mislav Novokmet and Maja Pucic-Bakovic 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 \{van den Heuvel\}, Tim and Daisy Jonkers and Marieke Pierik and \{IBD BIOM consortium\} and \{IBD Character Consortium\}",

note = "Funding Information: Stephanie Scott and Colette McColl for their help with the administrative aspects of this project. The study has been funded by the following EU FP7 grants: European Commission IBD-BIOM (contract \# 305479); IBD-CHARACTER (contract \# 2858546). NAK is funded by the Wellcome Trust (grant number WT097943MA). Publisher Copyright: {\textcopyright} The Author(s) 2016.",

year = "2016",

month = nov,

day = "25",

doi = "10.1038/ncomms13507",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Ventham, NT, Kennedy, NA, Adams, AT, Kalla, R, Heath, S, O'Leary, KR, Drummond, H, Wilson, DC, Gut, IG, Nimmo, ER, Satsangi, J, 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, Akmacic, IT, Krištic, J, Vuckovic, F, Štambuk, J, Novokmet, M, Pucic-Bakovic, 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, van den Heuvel, T, Jonkers, D , Pierik, M, 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 - 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 - Akmacic, Irena Trbojevic

AU - Krištic, Jasminka

AU - Vuckovic, Frano

AU - Štambuk, Jerko

AU - Novokmet, Mislav

AU - Pucic-Bakovic, 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 - van den Heuvel, Tim

AU - Jonkers, Daisy

AU - Pierik, Marieke

AU - IBD BIOM consortium

AU - IBD Character Consortium

N1 - Funding Information: Stephanie Scott and Colette McColl for their help with the administrative aspects of this project. The study has been funded by the following EU FP7 grants: European Commission IBD-BIOM (contract # 305479); IBD-CHARACTER (contract # 2858546). NAK is funded by the Wellcome Trust (grant number WT097943MA). Publisher Copyright: © The Author(s) 2016.

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.

U2 - 10.1038/ncomms13507

DO - 10.1038/ncomms13507

M3 - Article

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

Abstract

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