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Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci | BMC Medical Genetics | Full Text

Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci | BMC Medical Genetics | Full Text

Biomed Central



BMC Medical Genetics

Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci

  • Hamid Reza Saadati,
  • Michael Wittig,
  • Ingo Helbig,
  • Robert Häsler,
  • Carl A. Anderson,
  • Christopher G. Mathew,
  • Limas Kupcinskas,
  • Miles Parkes,
  • Tom Hemming Karlsen,
  • Philip Rosenstiel,
  • Stefan Schreiber and
  • Andre FrankeEmail author
BMC Medical GeneticsBMC series – open, inclusive and trusted201617:26
DOI: 10.1186/s12881-016-0289-z
Received: 10 November 2015
Accepted: 23 March 2016
Published: 1 April 2016

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 RNF216ZNF815OCM 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.

Keywords

Ulcerative colitis Copy number variation Rare variants SNP array Case-control association

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