Post

It's been 30 years (!!!) since the conceptualization of GWAS. GWAS has driven tons of discoveries, but with recent experimental developments (CRISPR, single-cell omics), we thought it was time to think about how to drive the next 30 years of human genetics. doi.org/10.5281/zeno...

We argue that the goal of human genetics should be to build *Trait Causal Models*. TCMs are quantitative, predictive models that trace the biological processes from genes --> traits.

TCMs should be: - Mechanistic: a model capturing the mechanisms by which genes affect a trait should be able to convert knowledge about how a perturbation or variant affects an intermediate phenotype into predictions about how it would affect the trait.

To build TCMs will require 3 distinct "data pillars", each with complementary advantages 1. Genetic association data (e.g., GWAS) 2. Perturbations in model systems (e.g., perturb-seq in cell lines) 3. Human subjects omics profiling (e.g., scRNA-seq from cases and controls).

There have been incredible advances across all 3 of these data pillars, but we discuss what more needs to be done to move from these pillars to building TCMs.