The Type I Diabetes Genetics Consortium 'Rapid Response' family-based candidate gene study: strategy, genes...

Candidate gene studies have long been the principal method for identification of susceptibility genes for type I diabetes (T1D), resulting in the discovery of HLA, INS, PTPN22, CTLA4, and IL2RA. However, many of the initial studies that relied on this strategy were largely underpowered, because of the limitations in genomic information and genotyping technology, as well as the limited size of available cohorts. The Type I Diabetes Genetic Consortium (T1DGC) has established resources to re-evaluate earlier reported genes associated with T1D, using its collection of 2298 Caucasian affected sib-pair families (with 11 159 individuals). A total of 382 single-nucleotide polymorphisms (SNPs) located in 21 T1D candidate genes were selected for this study and genotyped in duplicate on two platforms, Illumina and Sequenom. The genes were chosen based on published literature as having been either 'confirmed' (replicated) or not (candidates). This study showed several important features of genetic association studies. First, it showed the major impact of small rates of genotyping errors on association statistics. Second, it confirmed associations at INS, PTPN22, IL2RA, IFIH1 (earlier confirmed genes), and CTLA4 (earlier confirmed, with distinct SNPs) loci. Third, it did not find evidence for an association with T1D at SUMO4, despite confirmed association in Asian populations, suggesting the potential for population-specific gene effects. Fourth, at PTPN22, there was evidence for a novel contribution to T1D risk, independent of the replicated effect of the R620W variant. Fifth, among the candidate genes selected for replication, the association of TCF7-P19T with T1D was newly replicated in this study. In summary, this study was able to replicate some genetic effects, reject others, and provide suggestions of association with several of the other candidate genes in stratified analyses (age at onset, HLA status, population of origin). These results have generated additional interesting functional hypotheses that will require further replication in independent cohorts.