title: A functional methylome map of ulcerative colitis.
abstract: The etiology of inflammatory bowel diseases is only partially explained by the current genetic risk map. It is hypothesized that environmental factors modulate the epigenetic landscape and thus contribute to disease susceptibility, manifestation, and progression. To test this, we analyzed DNA methylation (DNAm), a fundamental mechanism of epigenetic long-term modulation of gene expression. We report a three-layer epigenome-wide association study (EWAS) using intestinal biopsies from 10 monozygotic twin pairs (n = 20 individuals) discordant for manifestation of ulcerative colitis (UC). Genome-wide expression scans were generated using Affymetrix UG 133 Plus 2.0 arrays (layer 1). Genome-wide DNAm scans were carried out using Illumina 27k Infinium Bead Arrays to identify methylation variable positions (MVPs, layer 2), and MeDIP-chip on Nimblegen custom 385k Tiling Arrays to identify differentially methylated regions (DMRs, layer 3). Identified MVPs and DMRs were validated in two independent patient populations by quantitative real-time PCR and bisulfite-pyrosequencing (n = 185). The EWAS identified 61 disease-associated loci harboring differential DNAm in cis of a differentially expressed transcript. All constitute novel candidate risk loci for UC not previously identified by GWAS. Among them are several that have been functionally implicated in inflammatory processes, e.g., complement factor CFI, the serine protease inhibitor SPINK4, and the adhesion molecule THY1 (also known as CD90). Our study design excludes nondisease inflammation as a cause of the identified changes in DNAm. This study represents the first replicated EWAS of UC integrated with transcriptional signatures in the affected tissue and demonstrates the power of EWAS to uncover unexplained disease risk and molecular events of disease manifestation.
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, 24105 Germany.
authors: Robert
authors: R
authors: Häsler
authors: Zhe
authors: Z
authors: Feng
authors: Liselotte
authors: L
authors: Bäckdahl
authors: Martina E
authors: ME
authors: Spehlmann
authors: Andre
authors: A
authors: Franke
authors: Andrew
authors: A
authors: Teschendorff
authors: Vardhman K
authors: VK
authors: Rakyan
authors: Thomas A
authors: TA
authors: Down
authors: Gareth A
authors: GA
authors: Wilson
authors: Andrew
authors: A
authors: Feber
authors: Stephan
authors: S
authors: Beck
authors: Stefan
authors: S
authors: Schreiber
authors: Philip
authors: P
authors: Rosenstiel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D056426:Genetic Loci; D015894:Genome, Human; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D014430:Twins, Monozygotic / Q000235:genetics