Saadati, H. R., Wittig, M., Helbig, I., Hasler, R., Anderson, C. A., Mathew, C. G., Kupcinskas, L., Parkes, M., Karlsen, T. H., Rosenstiel, Philip, Schreiber, Stefan and Franke, A. (2016) Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci. BMC Medical Genetics, 17 . DOI 10.1186/s12881-016-0289-z.

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Abstract

Background: Ulcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants. Methods: One thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication. Results: Twenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43 % cases, 0.11 % controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13 % cases, 0.01 % controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22 % carriers among cases, 0.03 % carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation. Conclusion: Our study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC.

Document Type:	Article
Additional Information:	Times Cited: 0 Saadati, Hamid Reza Wittig, Michael Helbig, Ingo Haesler, Robert Anderson, Carl A. Mathew, Christopher G. Kupcinskas, Limas Parkes, Miles Karlsen, Tom Hemming Rosenstiel, Philip Schreiber, Stefan Franke, Andre
Keywords:	Ulcerative colitis Copy number variation Rare variants SNP array Case-control association
Research affiliation:	Kiel University > Kiel Marine Science OceanRep > The Future Ocean - Cluster of Excellence Kiel University
Refereed:	Yes
Open Access Journal?:	Yes
Publisher:	Nature Research
Projects:	Future Ocean
Date Deposited:	01 Mar 2017 08:56
Last Modified:	13 Jun 2019 13:40
URI:	https://oceanrep.geomar.de/id/eprint/36291

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