Abstract
Crohn’s Disease (CD) is one of the predominant forms of inflammatory bowel disease (IBD). A combination of genetic and non-genetic risk factors have been reported to contribute to the development of CD. Many high-throughput omics studies have been conducted to identify disease associated risk variants that might contribute to CD, such as genome-wide association studies (GWAS) and next generation sequencing studies. A pressing need remains to prioritize and characterize candidate genes that underlie the etiology of CD. In this study, we collected a comprehensive multi-dimensional data from GWAS, gene expression, and methylation studies and generated transcriptome-wide association study (TWAS) data to further interpret the GWAS association results. We applied our previously developed method called mega-analysis of Odds Ratio (MegaOR) to prioritize CD candidate genes (CDgenes). As a result, we identified consensus sets of CDgenes (62–235 genes) based on the evidence matrix. We demonstrated that these CDgenes were significantly more frequently interact with each other than randomly expected. Functional annotation of these genes highlighted critical immune-related processes such as immune response, MHC class II receptor activity, and immunological disorders. In particular, the constitutive photomorphogenesis 9 (COP9) signalosome related genes were found to be significantly enriched in CDgenes, implying a potential role of COP9 signalosome involved in the pathogenesis of CD. Finally, we found some of the CDgenes shared biological functions with known drug targets of CD, such as the regulation of inflammatory response and the leukocyte adhesion to vascular endothelial cell. In summary, we identified highly confident CDgenes from multi-dimensional evidence, providing insights for the understanding of CD etiology.
Highlights
Crohn’s Disease (CD) is one of the major forms of inflammatory bowel disease (IBD)
We collected the summary statistics from a GWA study for CD conducted by the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) (Liu et al, 2015)
We focused on Gene Ontology (GO) and genetics association database (GAD) (Fresno and Fernandez, 2013)
Summary
Crohn’s Disease (CD) is one of the major forms of inflammatory bowel disease (IBD). CD has a prevalence of 26 to 200 per 100,000 person in populations with European ancestry (Loftus, 2004). A number of transcriptome profiling studies have been conducted, revealing genes that were differentially expressed in CD compared to controls, such as IFITM1 (Interferon Induced Transmembrane Protein 1), STAT1 (Signal Transducer And Activator Of Transcription 1), TAP1 (Transporter 1, ATP Binding Cassette Subfamily B Member), and PSMB8 (Proteasome Subunit Beta 8) identified using endoscopic pinch biopsies (Wu et al, 2007) and SERPINB2 (Serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 2, PAI 2), NCK2 (NCK Adaptor Protein 2), and ITGB3 (Integrin Subunit Beta 3) identified using peripheral blood mononuclear cell (PBMC) (Burczynski et al, 2006) Each of these unbiased, GWAS have provided unique insights and candidate pathogenic variants and genes to understand the etiology of CD. Challenges remain in how to effectively integrate these heterogeneous association data that range in a wide variety of biological processes
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