Trait Causal Models: from GWAS, perturbations, and omics to predictive models of human biology

A central goal of human genetics is to understand the molecular pathways that link genes to functions in cells and tissues, and ultimately to their roles in health and disease. Genome-wide association studies (GWAS) provide a unique — and powerful — tool for finding causal relationships between variants or genes and human traits, yet it remains challenging to gain mechanistic insights from these associations at genome scale. Here, we argue that recent advances in high-throughput perturbation methods and observational “omics” studies provide valuable complementary data that will be crucial for building the next generation of models in human genetics: formal models linking genes to pathways to cell and tissue biology to traits. These models should be mechanistic, causal, and predictive. We refer to such models as Trait Causal Models.