Linking GWAS risk genes to transcriptional features of major depressive disorder via in vivo Perturb-seq.

Major depressive disorder (MDD) is a complex disorder with numerous risk genes identified through genome-wide association studies, but their in vivo functions remain unclear. Here we built an in vivo adeno-associated virus (AAV)-Perturb-seq system to perform parallel loss-of-function screening of MDD risk genes in the mouse brain and to define their transcriptional effects and functional relationships. By comparing perturbation profiles with transcriptomic data from patients with MDD, we identified a cluster of risk genes whose loss led to neuronal downregulation of oxytocin signaling, a feature shared with patients with MDD. Mechanistic studies using Dennd1a as an example revealed that its neuron-specific downregulation impaired the oxytocin receptor-extracellular signal-regulated kinase pathway and induced depressive-like behaviors in mice. Pharmacological enhancement of this pathway alleviated depressive-like phenotypes in Dennd1a-deficient mice and restored oxytocin signaling in DENND1A-deficient human neurons, highlighting the importance of patient stratification for targeted treatment in complex diseases such as psychiatric disorders.