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BMC Medical Genetics

, 17:26

Genetic epidemiology and genetic associations

Abstract

BackgroundUlcerative 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.

MethodsOne 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.

ResultsTwenty-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.

ConclusionOur 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.

KeywordsUlcerative colitis Copy number variation Rare variants SNP array Case-control association Electronic supplementary materialThe online version of this article doi:10.1186-s12881-016-0289-z contains supplementary material, which is available to authorized users.

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Author: Hamid Reza Saadati - Michael Wittig - Ingo Helbig - Robert Häsler - Carl A. Anderson - Christopher G. Mathew - Limas Ku

Source: https://link.springer.com/







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