A functional methylome map of ulcerative colitis

• DOI: 10.1101/gr.138347.112
• Publication Date: 2012-07-24T03:02:51Z
• Authors: Robert Häsler; Zhe Feng; Liselotte Bäckdahl; Martina E. Spehlmann; Andre Franke; Andrew Teschendorff; Vardhman K. Rakyan; Thomas A. Down; Gareth A. Wilson; Andrew Feber; Stephan Beck; Stefan Schreiber; Philip Rosenstiel
• Keywords: Adult; Male; 0301 basic medicine; Genome-wide association study; Adolescent; Genetic loci; Twins; Ulcerative; Monozygotic; Epigenesis, Genetic; 03 medical and health sciences; Genetic; Humans; Middle aged; Aged; Genome; Genome, Human; Research; Sequence analysis; High-Throughput Nucleotide Sequencing; DNA; Sequence Analysis, DNA; Twins, Monozygotic; DNA Methylation; Middle Aged; Colitis; 3. Good health; Genetic Loci; Colitis, Ulcerative; Female; High-throughput nucleotide sequencing; Epigenesis; Human; Genome-Wide Association Study

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 incisof 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 factorCFI, the serine protease inhibitorSPINK4, and the adhesion moleculeTHY1(also known asCD90). 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.