Genome-wide analysis identifies rare copy number variations associated with inflammatory bowel disease.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
22
11
2018
accepted:
20
05
2019
entrez:
12
6
2019
pubmed:
12
6
2019
medline:
11
2
2020
Statut:
epublish
Résumé
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.
Sections du résumé
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
Our results revealed new genomic loci associated with IBD, which suggested the role of rare CNVs in IBD risk.
Identifiants
pubmed: 31185018
doi: 10.1371/journal.pone.0217846
pii: PONE-D-18-33615
pmc: PMC6559655
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0217846Déclaration de conflit d'intérêts
In the past four years, Dr Bernstein has consulted to or served on advisory boards of Abbvie Canada, Shire Canada, Takeda Canada, Pfizer Canada, Janssen Canada, Ferring Canada, Napo Pharmaceuticals and Mylan Pharmaceuticals. In addition, he has received educational grants from Abbvie Canada, Janssen Canada, Shire Canada and Takeda Canada. He has been speaker’s bureaus of Abbvie Canada, Shire Canada, Ferring Canada and Medtronic Canada. Dr Scherer is on the Scientific Advisory Committees of Population Bio and Deep Genomics. The other authors declare no conflict of interest for this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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