Identification, characterization, and validation of disease susceptibility loci from high-throughput sequencing and high-density microarray data.

The goal of this project is to study the impact of genetic variation on disease risk. The primary focus of the study is the search for rare genetic variants that place individuals at higher risk of developing one or more cancers, including breast, colorectal, ovarian, pancreatic, and prostate cancer as well as cholangiocarcinoma, hepatocellular carcinoma, soft-tissue sarcoma, and childhood cancers. The aims of the proposal are to 1) validate candidate genes and variants identified in other studies, 2) to identify new candidate genes, 3) to estimate the risk of developing disease for individuals with rare disease-causing variants, 4) to identify and validate regions of the genome associated with disease by examining recent genetic ancestry, 5) to evaluate whether disease-causing variants interact with the environment and each other, and 6) to develop new methods and software that can be used to support the first five aims. The project is motivated by numerous examples of rare variants that increase the risk of developing particular diseases by harming gene function. Because this project will support multiple ongoing studies, we are requesting the maximum project duration of 36 months with rolling renewal. The impacts of the project will be to improve our understanding of the biology of multiple human diseases and to predict whether individuals will develop specific diseases by examining genetic information. These predictions can contribute to more effective early detection and screening as well as improved diagnosis and treatment.