Some individuals that appear to be at high risk of developing disease based on their genes never develop or have a mild form of disease. We want to identify genes that protect people in the UK Biobank at high genetic risk from getting disease. Genes that protect individuals from disease will be prioritized for further experiments to understand the biological mechanism. Understanding the disease modifying or protective mechanism will improve our ability to develop effective therapies for human diseases. In parallel, we will be performing experiments using laboratory assays that model specific aspects of human disease using new methodologies to inactivate genes in a high-throughput manner. We seek to identify genes that alter known pathogenic mechanisms. We will then determine if variants from genes that protect from disease in a 'test tube' protect UK Biobank participants from disease.