Type 1 Diabetes Genetics Consortium (T1DGC): ImmunoChip Study

The 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 cases and controls were ascertained from existing and de novo collections. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, T1D cases from the UK Genetic Resource Investigating Diabetes (UKGRID, N=6,670), and controls from the British 1958 Birth Cohort (B58BC, N=6,523), the UK National Blood Services collection (NBS, N=2,893) and the NIHR Cambridge Biomedical Research Centre BioResource (CBR, N=2,846). 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. Genotyping was performed using a custom Illumina Infinium high-density genotyping array, ImmunoChip (Illumina, Inc; CA) according to manufacturer's protocols. The ImmunoChip was designed to densely genotype, using 1000 Genomes and any other available disease specific resequencing data, immune-mediated disease loci identified by common variant GWAS. The ImmunoChip Consortium selected 186 distinct loci containing markers meeting genome wide significance criteria (P<5x10-8) from twelve such diseases (autoimmune thyroid disease, ankylosing spondylitis, Crohn's disease, celiac disease, IgA deficiency, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, T1D and ulcerative colitis). All 1000 Genomes Project pilot phase CEU population variants (Sept 2009 release) within 0.1cM (HapMap3 CEU) recombination blocks around each GWAS region lead marker were submitted for array design. No filtering on correlated variants (linkage disequilibrium) was applied. Additional content included regional resequencing data (submitted by several groups) as well as a small proportion of investigator-specific undisclosed content including intermediate GWAS results. After data cleaning and quality control, a total of 154,939 single nucleotide polymorphisms (SNPs) from 186 loci on ImmunoChip were scored. Case-control and family data were analyzed independently and combined by meta-analysis.

• Study Weblinks:
  • T1D Base
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
  • Affected Sib Pairs
  • Parent-Offspring Trios
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 17460
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• Sequence Read Archive
• BioSample
• MeSH
• PMC

To be included in the study, a family had to have at least one ASP available for sampling; availability of one or both biological parents was preferred but not required. For families, trios and cases, 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.

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.

• Primary Phenotype: Diabetes Mellitus, Type 1
• Autoimmune Diseases
• Autoantibodies

• Principal Investigator
  • Stephen S. Rich, PhD. University of Virginia, Charlottesville, VA, USA.
• Funding Sources
  • U01-DK062418, JDRF. National Institutes of Health, Bethesda, MD, USA; Juvenile Diabetes Research Foundation, New York, NY, USA.
• Co-Investigators
  • John A. Todd, PhD. University of Cambridge, UK.
  • Pat Concannon, PhD. University of Florida, Gainesville, FL, USA.
  • Suna Onengut-Gumuscu, PhD. University of Virginia, Charlottesville, VA, USA.
  • Chris Wallace, PhD. University of Cambridge, UK.
  • Wei-Min Chen, PhD. University of Virginia, Charlottesville, VA, USA.
  • Oliver Burren, BS. University of Cambridge, UK.