Type 1 Diabetes Genetics Consortium (T1DGC): Copy Number Variant (CNV) Study

Type 1 Diabetes Genetics Consortium (T1DGC) was formed to address issues of limited sample size and consistency of phenotyping that had limited genetic investigations on risk of type 1 diabetes (T1D). The T1DGC first collected affected sib pair (ASP) families from four geographic networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, T1D parent-offspring trios as well as cases and controls were ascertained from existing and de novo collections. For T1D, the genome-wide association study (GWAS) design has been successful at detecting ~50 loci that contribute disease risk. However, in the case of T1D as well as almost all other traits, the sum of these loci does not fully explain the heritability estimated from familial studies. One possibility for the undiscovered contribution to familial aggregation is that additional variants exist but have not yet been found because they have not effectively been targeted by the GWAS design. In this study, we focus on a specific class of large deletions/duplications -- copy number variants (CNVs) - and particularly to the subset of these loci that mutate rapidly, are not tagged by SNPs, and are highly polymorphic. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, that were eligible for this study. All samples included in this series have reported or self-declared European ancestry. All DNA samples were collected after approval from relevant institutional research ethics committees. Importantly, the source of DNA for CNV evaluation was uniform within a family (either all from PBMC or from EBV-transformed cell lines). We use a family based design that was optimized to capture these previously untested variants. We then perform a genome-wide scan to assess their contribution to T1D.]]>
To be included in the study, an affected sibpair (ASP) family had to have at least one ASP available for sampling; availability of one or both biological parents; and the same source (blood or cell line) of DNA for all family members. For parent-offspring trio families, all three members (both paretns and the T1D-affected offspring was required to have the same source of DNA (blood or cell line). An individual was designated as affected with type 1 diabetes (T1D) if he or she had documented T1D with onset at <35 years of age, had used insulin within 6 months of diagnosis, and had no concomitant disease or disorder associated with diabetes. Preference was given to those families having participants with ImmnoChip genotyping.]]>
The Type 1 Diabetes Genetics Consortium (T1DGC) is an international effort to identify genes that determine an individual's risk of type 1 diabetes (T1D). A major effort of the T1DGC was the creation of a resource base of well-characterized families, trios, cases and controls from multiple ethnic groups that will facilitate the localization and characterization of T1D susceptibility genes. Building upon these T1DGC resources, members and collaborators of the T1DGC have undertaken multiple candidate gene and genome-wide efforts to identify genes and variants that determine susceptibility or protection to T1D. The T1DGC was established through the efforts of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Juvenile Diabetes Research Foundation (JDRF). Participation in Consortium activities was available to all investigators who sign a Consortium Agreement that explained the rights and responsibilities of T1DGC members. The governance of the T1DGC, including scientific agenda, assessment of recruitment, quality control of assays, dissemination of study results, and provision of training and technology transfer, was advised by the T1DGC Steering Committee (Stephen S Rich, PhD, PI and Chair of the Steering Committee), with support from the programmatic advisors (NIDDK, JDRF), observers (NIAID, NHGRI, Diabetes UK) and External Advisory Board (EAB). The T1DGC initially identified existing resources of ASP families (~1400) with appropriate consents, the T1DGC then established recruiting networks to obtain an additional ~2500 ASP families and parent-offspring trio families throughout the world. The T1DGC developed four regional networks: North America (NA), Europe (EU), United Kingdom (UK), and Asia-Pacific (AP). Recruitment targets varid by network: AP and UK networks each collected ~200 ASP families, while EU and NA networks each collected ~1200 ASP families. Each network established a recruitment center and staff, and each used multiple approaches to recruit volunteers. Within each network, field centers identified, ascertained, and collected samples and data from participating families. The large number of samples and the international locations of the networks required that the T1DGC established laboratories in multiple sites. Each network established a DNA repository (to process samples for DNA, and to provide cell immortalization), an HLA laboratory (to determine classical HLA typing), and an autoantibody laboratory (to characterize plasma from cases). The T1DGC Coordinating Center (at Wake Forest University) established a system of sample transfer and tracking to the T1DGC laboratories and was the central repository of clinical information and genetic data. All samples and data from the T1DGC network laboratories have been transferred to NIDDK repositories (data, plasma and serum, and cell lines) or dbGaP/EGA from which investigators can make requests. The T1DGC completed three genome-wide linkage scans, a GWAS meta-analysis, an intensive evaluation of risk derived from fine-mapping the human MHC, and an evaluation of candidate gene variants (from T1D and T2D) on T1D risk. More recently, the T1DGC has supported fine mapping of T1D GWAS loci (through the ImmunoChip) and an intensive investigation of the role of copy number variants (CNVs) not tagged by SNPs.]]>