Zeyu YANG

Disease predisposition arises from complex, multivariate gene regulation, yet conventional approaches typically nominate a single target gene and fail to capture the underlying regulatory network. Two complementary genome-scale resources now make the full network tractable: genome-wide CRISPRi Perturb-seq, which reveals how knocking down any individual gene reshapes the entire transcriptional program landscape, and human loss-of-function (LoF) genetics, which quantifies how a gene's inactivation affects a disease trait. Inspired by a recent Nature framework (Ota et al.), we integrate these to reconstruct, for a chosen disease, a directed network linking regulator genes to gene-expression programs and ultimately to the trait. We demonstrate it on rheumatoid arthritis (RA): non-negative projection of CD4⁺ T-cell Perturb-seq onto RA patient–derived programs, followed by a program-to-trait regression against RA LoF burden, yields the complete regulator→program→trait map. The network recovers the Th17 program—a hallmark pathogenic CD4⁺ T-cell state in RA—as a positive control, and additionally surfaces the SOCS2/CISH cytokine-signalling-feedback program (P19) and its candidate upstream regulators as a novel, testable lead. Finally, we release a reproducible, disease-swappable pipeline, letting the same framework be applied to any trait with matched Perturb-seq and LoF data.