Research Article: Genome-wide analysis identifies rare copy number variations associated with inflammatory bowel disease

Date Published: June 11, 2019

Publisher: Public Library of Science

Author(s): Svetlana Frenkel, Charles N. Bernstein, Michael Sargent, Qin Kuang, Wenxin Jiang, John Wei, Bhooma Thiruvahindrapuram, Elizabeth Spriggs, Stephen W. Scherer, Pingzhao Hu, Vincenzo De Luca.


Inflammatory bowel disease (IBD) is an idiopathic, chronic disorder of unclear etiology with an underlying genetic predisposition. Recent genome-wide association studies have identified more than 200 IBD susceptibility loci, but the causes of IBD remain poorly defined. We hypothesized that rare (<0.1% population frequency) gene copy number variations (CNVs) could play an important mechanism for risk of IBD. We aimed to examine changes in DNA copy number in a population-based cohort of patients with IBD and search for novel genetic risk factors for IBD. DNA samples from 243 individuals with IBD from the Manitoba IBD Cohort Study and 2988 healthy controls were analyzed using genome-wide SNP microarray technology. Three CNV calling algorithms were applied to maximize sensitivity and specificity of CNV detection. We identified IBD-associated genes affected by rare CNV from comparing the number of overlapping CNVs in IBD samples with the number of overlapping CNVs in controls for each gene. 4,402 CNVs detected by two or three algorithms intersected 7,061 genes, in at least one analyzed sample. Four genes (e.g. DUSP22 and IP6K3) intersected by rare deletions and fourteen genes (e.g. SLC25A10, PSPN, GTF2F1) intersected by rare duplications demonstrated significant association with IBD (FDR-adjusted p-value < 0.01). Of these, ten genes were functionally related to immune response and intracellular signalling pathways. Some of these genes were also identified in other IBD related genome-wide association studies. These suggested that the identified genes may play a role in the risk of IBD. Our results revealed new genomic loci associated with IBD, which suggested the role of rare CNVs in IBD risk.

Partial Text

Inflammatory bowel disease (IBD) is a chronic, progressive and often disabling inflammatory disorder of the gastrointestinal tract associated with dysregulation in both the intestinal immune system and the intestinal microbiota. IBD affects more than 1.5 million people in North America and about 2.5 millions of Europeans with a rising incidence in developing countries.[1,2] Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of IBD, both of which are characterised by variations in age of onset, severity of symptoms, disease phenotype, as well as response to treatments.

In the current study, we investigated rare genic CNVs detected by genome-wide high-resolution microarray technology in a cohort of 243 IBD patients and 2,988 control samples. Of all CNVs identified simultaneously by at least two computational algorithms, 65% were deletions. This imbalance is most likely related to the detection bias of SNP-based array platforms leading to the missing of duplications.[9,28] 35% of the deletions overlapped one or more genes, while the proportion of gene-overlapping duplications reached 64%. This difference can be explained by lower negative selective pressure on duplications than on deletions because of their milder phenotypic effect.[8] About 88% of the discovered CNVs were less than 100kbp in size. Although the burden of short CNVs, especially short deletions, was significantly higher in the group of samples with CD than with UC, such difference was not observed in the burden of all CNVs in CD and UC (see Table 1), suggesting that overall CNV burden did not differ significantly between IBD subtypes. Although we detected the CNVs more frequent in controls compared with the IBD patients, the overall CNV burden did not significantly differ in the IBD patients compared with the controls in all of the CNV length types, except the largest CNV length type (>1 Mbp), where the burden of the large CNVs in the IBD patients is significantly higher than that in the controls (p-value = 0.002, OR = 2.8 and 95% CI: 1.4–5.2).




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