Comparing Design Approaches for Sequencing Disease-Associated Regions found in Genome-Wide Association Studies (U01)

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Purpose. Genome-wide association studies (GWAS) have identified many genomic regions associated with common diseases and other traits. The next step often is to sequence many samples in the associated regions to determine their complete patterns of genetic variation. The goal is to identify a smaller set of strongly associated variants for more intense study to find those responsible for the increased disease risk. Various design strategies could be used for the sequencing studies, such as sequencing exons or entire gene regions, and using samples from the extremes or the entire range of the phenotype distribution. However, the appropriate conditions for using particular design strategies are unknown. To gain insight into optimal study design, NHGRI will support several studies to sequence association regions completely in large GWAS cohorts to provide standard datasets and analyses that the research community can use to study how to design sequencing studies to follow up GWAS findings. This FOA solicits applications from investigators with well-replicated disease associations to nominate association regions for sequencing and analysis and to provide a sufficient number of samples with genotype, phenotype, and exposure datasets from completed GWA studies. The sequencing capacity will be provided by the NHGRI large-scale sequencing centers, using a broad design strategy that encompasses a number of more focused strategies. Funding for analysis of the sequence data will be provided by the Genes, Environment, and Health Initiative (GEI). The funded GWAS groups will work in a consortium with the sequencing centers and analysts to develop the broad design strategy, analyze the sequence data for the individual studies, and evaluate the various specific design strategies.

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