T2D-GENES Consortium

T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) is an NIDDK-funded research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES is currently undertaking two sequencing studies and one GWAS-based fine-mapping study.

Project 1 seeks to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. Project 1 is carrying out deep exome sequencing of 10,000 individuals, 5,000 with T2D and 5,000 controls, equally divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing is underway at the Broad Institute using the Agilent v2 capture reagent on HiSeq machines.

Project 2 is focused on the role of rare and private variants on T2D risk, and is based on deep whole genome sequencing of ~600 members of 20 Mexican American pedigrees. Pedigree members are extensively phenotyped and have been genotyped with Illumina GWAS chips. By applying an algorithm for efficient choice of individuals to sequence and highly-accurate pedigree-based imputation methods we will have the equivalent of ~1,100 sequenced individuals. Because of large family size, even private variants are likely to be present multiple times, allowing an assessment of the impact of such variants currently impractical in case-control or population studies. Sequence data on all but ~40 individuals has been delivered by Complete Genomics (CGI); the remainder are expected soon.

Project 3 seeks to determine whether multiethnic GWAS meta-analysis might assist in fine-mapping T2D association signals by strengthening evidence for T2D association and narrowing the association interval. Project 3 has focused initially on analysis of five T2D loci chosen as likely candidates for success of this approach.