Systematic analysis of genomic copy number variations in inflammatory bowel diseases

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) which are characterized by excessive immune responses to gut microbial flora in genetically susceptible individuals. A comprehensive dissection of the genetic predisposition to IBD needs to assess the contribution of all types of genetic variants including copy number variations (CNVs) to disease risk. In the presented thesis, two related studies were conducted to interrogate the presence of disease-relevant CNVs; In one, SNP-GWAS data-set of a German UC cohort together with four other independent UC case control series were recruited to perform a multi-step genome-wide association analysis. Three CNVs enriched in UC patients were identified; a 15.8 kb deletion upstream of the genes ABCC4 and CLDN10 at 13q32.1, a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3. Most of these candidate genes have been functionally implicated in inflammatory processes. The probable effects of Del 13q32.1 on expression of the two nearby genes were examined in intestinal biopsies of a UC patient panel. In parallel, genomic DNA from peripheral blood as well as intestinal biopsies from nine monozygotic twin pairs discordant for IBD manifestations (4 CD, 5 UC) were recruited and compared for genome-wide CNVs by means of array-CGH, quantitative PCR and sequencing. Initial CNV calls were also contrasted with expression data of the affected genes in the corresponding twin samples. No consistent copy number differences were however revealed in the genomic DNA of discordant twins. The results implicated the potential contribution of germline structural variants to the risk of UC. Post-zygotic genomic CNVs, however, appear not to be the common cause of IBD-discordance in MZ twins



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