title: Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Saadati
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wittig
authors.affiliation: Department of Neuropediatrics, University Clinic Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, Building 9, 24105, Kiel, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
authors.affiliation: Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.affiliation: Institute for Digestive Research, Lithuanian University of Health Sciences, Mickeviciaus 9, Kaunas, LT, 44307, Lithuania.
authors.forename: Limas
authors.initials: L
authors.lastname: Kupcinskas
authors.affiliation: Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.affiliation: Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital, Rikshospitalet, 0027, Oslo, Norway.
authors.forename: Tom Hemming
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.|Department of Internal Medicine, University Hospital Schleswig-Holstein, Schittenhelmstraße 12, 24105, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany. a.franke@mucosa.de.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
keywords: Case-control association; Copy number variation; Rare variants; SNP array; Ulcerative colitis