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Jeff Spence
@jeffspence.github.io

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...

doi.orgTrait Causal Models: from GWAS, perturbations, and omics to predictive models of human biologyA 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...
Jeff Spence
@jeffspence.github.io

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.

Jeff Spence
@jeffspence.github.io

TCMs should be: - Quantitative: we should move beyond just cataloging associations and instead we should estimate _by how much_ and _in which direction_ a variant or a perturbation would affect the trait

Jeff Spence
@jeffspence.github.io

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.

Jeff Spence
@jeffspence.github.io

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).

2 reposts6 likes

Jeff Spence
@jeffspence.github.io

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.

Jeff Spence
@jeffspence.github.io

Key challenges include: - Extracting directional, quantitative effects of _genes_ on traits from GWAS data - Choosing cell types and conditions and types of perturbations in screens - Choosing the right level of abstraction for modeling the path from variant --> trait

Jeff Spence
@jeffspence.github.io

We discuss all of this and more in the piece. It was a lot of fun thinking through how to use the data that we have and to try to crystallize what the goal of human genetics should be. We're hoping to spark a conversation so please let us know you're thoughts. doi.org/10.5281/zeno...

doi.orgTrait Causal Models: from GWAS, perturbations, and omics to predictive models of human biologyA 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...