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.
authors.affiliation: Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK.
authors.forename: N T
authors.initials: NT
authors.lastname: Ventham
authors.affiliation: Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK.
authors.forename: N A
authors.initials: NA
authors.lastname: Kennedy
authors.affiliation: Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK.
authors.forename: A T
authors.initials: AT
authors.lastname: Adams
authors.affiliation: Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK.
authors.forename: R
authors.initials: R
authors.lastname: Kalla
authors.affiliation: CNAG-CRG, Centro Nacional de Análisis Genómico, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, Barcelona 08028, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain.
authors.forename: S
authors.identifier: 0000-0002-9550-0897
authors.initials: S
authors.lastname: Heath
authors.affiliation: Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK.
authors.forename: K R
authors.initials: KR
authors.lastname: O'Leary
authors.affiliation: Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK.
authors.forename: H
authors.initials: H
authors.lastname: Drummond
authors.affiliation: Department of Child Life and Health, University of Edinburgh, Edinburgh EH9 1UW, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Wilson
authors.affiliation: CNAG-CRG, Centro Nacional de Análisis Genómico, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, Barcelona 08028, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain.
authors.forename: I G
authors.initials: IG
authors.lastname: Gut
authors.affiliation: Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Nimmo
authors.affiliation: Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 6XU, UK.
authors.forename: J
authors.initials: J
authors.lastname: Satsangi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000097:blood / Q000235:genetics*; D003424:Crohn Disease / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: C524940:MIRN21 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C526584:VMP1 protein, human; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases