Recent genetic studies have identified hundreds of susceptibility genes for common human diseases but genetic effects are small and identifying underlying mechanisms remains challenging. Rodent models offer significant advantages for analysis of disease phenotypes. Advances in genome resources and gene targeting have increased the attractiveness of the rat model for genetic studies but progress has been hampered by absence of relevant rat genome sequences.We recently sequenced the genome of the spontaneously hypertensive rat (SHR) and will shortly have completed the Wistar Kyoto (WKY) rat sequence. The SHR genome contains over 750 genes that are completely or partly deleted, or have a frameshift in their open reading frame. These sequence variants, along with variants controlling dysregulated gene expression that we characterised previously, most likely include the major determinants of SHR cardiovascular and metabolic disease phenotypes.We shall determine the functional consequences of these variants by creating and phenotyping transgenic and knockout rats on the SHR and WKY genetic backgrounds, using transposon-mediated transgenesis and zinc-finger nuclease-mediated gene deletion recently shown to be highly efficient in rats. Genes will be prioritised for study by statistical and informatic analyses using our extensive physiological, gene expression and linkage data in these rat strains, and by comparative analysis with data from human genome-wide association studies. Confirmed rat disease genes will be tested for conserved functions in humans.These proposals provide a systematic route to elucidating the molecular and functional basis of disease phenotypes in SHR and WKY rats, and for translating these findings to advance understanding of common human diseases.