title: A genome-wide assessment of the role of untagged copy number variants in type 1 diabetes.
abstract: Genome-wide association studies (GWAS) for type 1 diabetes (T1D) have successfully identified more than 40 independent T1D associated tagging single nucleotide polymorphisms (SNPs). However, owing to technical limitations of copy number variants (CNVs) genotyping assays, the assessment of the role of CNVs has been limited to the subset of these in high linkage disequilibrium with tag SNPs. The contribution of untagged CNVs, often multi-allelic and difficult to genotype using existing assays, to the heritability of T1D remains an open question. To investigate this issue, we designed a custom comparative genetic hybridization array (aCGH) specifically designed to assay untagged CNV loci identified from a variety of sources. To overcome the technical limitations of the case control design for this class of CNVs, we genotyped the Type 1 Diabetes Genetics Consortium (T1DGC) family resource (representing 3,903 transmissions from parents to affected offspring) and used an association testing strategy that does not necessitate obtaining discrete genotypes. Our design targeted 4,309 CNVs, of which 3,410 passed stringent quality control filters. As a positive control, the scan confirmed the known T1D association at the INS locus by direct typing of the 5' variable number of tandem repeat (VNTR) locus. Our results clarify the fact that the disease association is indistinguishable from the two main polymorphic allele classes of the INS VNTR, class I-and class III. We also identified novel technical artifacts resulting into spurious associations at the somatically rearranging loci, T cell receptor, TCRA/TCRD and TCRB, and Immunoglobulin heavy chain, IGH, loci on chromosomes 14q11.2, 7q34 and 14q32.33, respectively. However, our data did not identify novel T1D loci. Our results do not support a major role of untagged CNVs in T1D heritability.
authors.affiliation: University College London (UCL) Genetics Institute (UGI), London, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zanda
authors.affiliation: University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Walker
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Corina
authors.initials: C
authors.lastname: Shtir
authors.affiliation: University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gallo
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Smyth
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: University College London (UCL) Genetics Institute (UGI), London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
mesh_terms: D000483:Alleles; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics