title: Detection and correction of artefacts in estimation of rare copy number variants and analysis of rare deletions in type 1 diabetes.
abstract: Copy number variants (CNVs) have been proposed as a possible source of 'missing heritability' in complex human diseases. Two studies of type 1 diabetes (T1D) found null associations with common copy number polymorphisms, but CNVs of low frequency and high penetrance could still play a role. We used the Log-R-ratio intensity data from a dense single nucleotide polymorphism (SNP) array, ImmunoChip, to detect rare CNV deletions (rDELs) and duplications (rDUPs) in 6808 T1D cases, 9954 controls and 2206 families with T1D-affected offspring. Initial analyses detected CNV associations. However, these were shown to be false-positive findings, failing replication with polymerase chain reaction. We developed a pipeline of quality control (QC) tests that were calibrated using systematic testing of sensitivity and specificity. The case-control odds ratios (OR) of CNV burden on T1D risk resulting from this QC pipeline converged on unity, suggesting no global frequency difference in rDELs or rDUPs. There was evidence that deletions could impact T1D risk for a small minority of cases, with enrichment for rDELs longer than 400 kb (OR = 1.57, P = 0.005). There were also 18 de novo rDELs detected in affected offspring but none for unaffected siblings (P = 0.03). No specific CNV regions showed robust evidence for association with T1D, although frequencies were lower than expected (most less than 0.1%), substantially reducing statistical power, which was examined in detail. We present an R-package, plumbCNV, which provides an automated approach for QC and detection of rare CNVs that can facilitate equivalent analyses of large-scale SNP array datasets.
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cooper
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Corina J
authors.initials: CJ
authors.lastname: Shtir
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Austin D
authors.initials: AD
authors.lastname: Swafford
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK, University College London, Darwin Building, London WC1E 6BT, UK.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zanda
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.affiliation: University College London, Darwin Building, London WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Cooper
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK, Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK.
authors.forename: Joanna M M
authors.initials: JM
authors.lastname: Howson
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Burren
authors.affiliation: Center for Public Health Genomics, West Complex, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Center for Public Health Genomics, West Complex, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK, john.todd@cimr.cam.ac.uk.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D000293:Adolescent; D016477:Artifacts; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D003627:Data Interpretation, Statistical; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques / Q000379:methods*; D006801:Humans; D011786:Quality Control; D012680:Sensitivity and Specificity; D017384:Sequence Deletion; D012984:Software