Causal modeling of gene effects from regulators to programs to traits: integration of genetic associations and Perturb-seq

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Genetic association studies provide a unique tool for identifying causal links from genes to human traits and diseases. However, it is challenging determine the biological mechanisms underlying most associations, we lack genome-scale approaches inferring mechanistic pathways cellular functions traits. Here propose new bridge this gap by combining quantitative estimates of gene-trait relationships loss-of-function burden tests with gene-regulatory connections inferred Perturb-seq experiments in relevant cell types. By these two forms data, aim build graphs which directional associations trait can be explained their regulatory effects on programs or direct trait. As proof-of-concept, constructed graph gene hierarchy that jointly controls three partially co-regulated blood We perturbation trait-relevant types, coupled gene-level effect sizes traits, between genetics biology.

Language: Английский

From CRISPR screens to circuits: identifying key regulators in T cell activation and state transitions

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: April 6, 2025

Language: Английский