Next-Generation Disease Association Analyses: Low pass Sequencing and High Density SNP genotyping for type 2 diabetes. (360G-Wellcome-090367_Z_09_Z)

This application, from groups in the UK and US, builds on an impressive record of productive collaboration on the genetic basis of type 2 diabetes (T2D) and related conditions, and in development of community resources and statistical methods for complex trait analyses. The research has two principal objectives. The first involves operational implementation and rigorous evaluation of alternative emerging strategies for the genome-wide detection and characterization of disease-risk variants, with a particular emphasis on low-frequency alleles poorly-captured by existing methods. To achieve this, we will undertake low-pass genome-wide resequencing and high-density genotyping (using a bespoke array) in 3000 well-studied T2D case-control samples. We will implement novel statistical and analytical approaches to gain strategic insights into the relative performance of these methods and to compare them against 1000 Genomes-based imputation. This information will be of generic value to resear chers and funders. Secondly, we will apply the data generated and insights gained to identify and characterise ( fine-map ) disease-risk variants. The initial focus will involve T2D, making use of over 100,000 samples ( > 50,000 with genome-wide association data) available to the applicants and collaborators: through collaborative and wider data-sharing, our work will also accelerate equivalent efforts for many other phenotypes of biomedical importance.