Genetic loci for complex traits such as coronary artery disease (CAD) are distributed widely across the genome, often mapping near genes with unclear connections to disease biology. The omnigenic model proposes that gene regulatory networks interconnect these loci in disease-relevant cells, allowing peripheral genes to influence a limited set of core effector pathways. To functionally investigate this architecture in adipose tissue, we applied a single-cell CRISPR perturbation platform to genetically prioritized CAD genes in human adipocytes. Perturbation of multiple candidate loci revealed structured transcriptional convergence on a program characterized by suppression of adipogenesis and activation of extracellular matrix remodeling. Network analysis identified a shared set of convergent core genes enriched for cardiometabolic pathways and druggable targets. Integration of perturbation results with human genetic analyses linked several core genes to lipid and metabolic traits, indicating that these intermediate phenotypes may mediate the effects of core genes' function in adipose remodeling on cardiometabolic disease risk.

Co-authors: Amos Romer, Sebastian Doetsch, Shuangyue Li, Ling Li, Moritz von Scheidt, Daniel Tews, Martin Wabitsch, Heribert Schunkert, Matthias Heinig, Zhifen Chen