Pancreatic adenocarcinoma (PaCa) is the 4th leading cause of cancer death in the United States and 8th leading cause worldwide. However, if caught at an early stage, there exist effective surgical treatments. A major difficulty with this is the lck established prevention and screening strategies. Here we propose to discover important genetic risk factors to aid in such a strategy, using exome and targeted sequencing of 4,400 pancreatic cases and 4,400 matched controls of European descent. To manage the cost of sequencing such large portions of the genome, we employ the following 2-stage study design, encompassing our first two aims: (1) deep discovery across whole exomes, followed by (2) targeted sequencing of genes deemed most promising in the first stage. This design retains high power (>90%) to identify genes with moderate risk variation for PaCa, based on the patterns of variation discovered in real studies of breast cancer. In our third aim (3) we propose to quantify somatic mutational load in genes identified from large studies of PaCa genomes, using existing tumor tissue. This somatic variation will be paired to whole-exomes sequenced in Aim 1 to elucidate host-tumor genomic interactions. Our proposed work leverages a strong environment of sample resources at MD Anderson Cancer Center and a well-constructed team of diverse expertise spanning fields of Epidemiology, Genomics, Pathology, Surgery and Computational Human Genetics. The analytical methods we propose will be conducted by leading experts in statistical genetics, who have made major contributions to the development of these techniques. Based on previous studies of familial aggregation of PaCa, and the relative paucity of findings to date from genome-wide association studies, we expect there to be numerous genes with rare variation of intermediate to high risk for PaCa. Given the epidemiological and demographic data, our 2-stage study design and large patient resource, our study is well powered for successful identification of these genes. These results will offer new insights in the etiology of this dreaded and deadly disease.