Type 1 Diabetes Genetics Consortium

Abstract

Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing β cells. Genetic factors account for approximately 50% of the risk for T1D but, by the late 1990s, the genetic basis was limited. The Type 1 Diabetes Genetics Consortium (T1DGC) was formed in 2002 to accelerate discovery of genes contributing to T1D risk through a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to assemble existing data and samples from affected sib-pair families and to establish new collections. In recognition of the 75th anniversary of the NIDDK, this manuscript highlights the contributions made by the T1DGC to understanding the genetic basis of T1D using both family (for linkage) and case-control (for genome-wide association) designs. The T1DGC conducted large-scale genetic research and used fine mapping to define risk regions. The T1DGC data, results, and samples have been made available to the scientific community, leading to the discovery of more than 100 loci associated with T1D risk, many with small effects and relevant to autoimmune pathways. The T1DGC not only expanded the list of genes contributing to disease risk but also identified noncoding genetic variation in disease-relevant cell types that contribute to the etiology of T1D. The success of the T1DGC and the NIDDK investment in the global consortium is highlighted in its continuing effect on mapping genetic variants to their function and identifying pathways that provide new targets for the prediction, prevention, and treatment of T1D.

Keywords: association; fine mapping; genetics; linkage; type 1 diabetes.

Figure 1.

Timeline of gene discovery in type 1 diabetes (T1D). The earliest genetic association with T1D occurred in 1973 (HL-A) with relatively few discoveries over the next 30 years (INS, CTLA4, PTPN22, IL2RA, IFIH1) until advances in genotyping technology and assembly of large case-control series (Wellcome Trust Case Control Consortium) stimulated discovery and fine mapping of genomic regions associated with T1D.

Figure 2.

Genes associated with type 1 diabetes (T1D) risk and protection. Current status of candidate genes associated with T1D risk, ranked by the size of their effect on risk. There are now more than 100 candidate genes in the human genome associated with T1D using data generated by the Type 1 Diabetes Genetics Consortium (10, 23, 28, 33, 49).