Millions of individuals have been sequenced or genotyped and linked with medical records, providing an exciting opportunity for therapeutic target discovery. My lab has been using a resilience approach to learn from success instead of failure, and analyzed hundreds of thousands of genomes with electronic medical records to drive target discovery for childhood Mendelian diseases, Alzheimer’s disease, and cardiovascular traits.

I will describe how we analyzed 589,305 genomes and identified 13 genetic super heroes who carry fully penetrant childhood Mendelian diseases but are healthy in our recent resilience project, and how we decoded individuals who carry APOE e4/e4 risk variants but are resilient for Alzheimer’s disease. I will further describe how we analyzed individuals who have a loss of gene but carry favorable cardiovascular traits, identified potential therapeutic targets to lower fasting glucose levels, and validated the effects in mice.

Learning objectives:

• How to interpret genetic variants using 150,000 genomes from diseased and healthy cohorts, and variants with validated molecular functional impact from 30 million literature.
• How to use resilient approach to interpret thousands of genomes with medical records for therapeutic target discovery.