From genes to programs to traits: Building causal models for human genetics with GWAS and perturb-seq

Genome-wide association studies (GWAS) provide a unique and powerful tool for identifying causal links from variants to genes to human traits and diseases. Although modern GWAS give an information-rich readout of the relevant variants and genes, it remains very challenging to turn this into mechanistic models of disease and clinical applications. In this talk I will describe how new genome-wide CRISPR-based perturbations provide a critical interpretive key for human genetics data, including our recent proof-of-concept study inferring causal graphs for red blood cell-related traits such as hemoglobin levels, and our new genome-wide perturb-seq of primary T cells in multiple stimulation contexts. I will close with a broader discussion of the opportunities and open challenges in this field.