Spatiotemporal dynamics of RERE in schizophrenia pathogenesis: insights from multi-omics and single-cell sequencing

Identification of cell type-specific and temporally dynamic regulatory features of schizophrenia (SCZ) risk genes is essential for advancing mechanistic neurobiological studies. This study systematically dissected the genetic architecture and neurodevelopmental mechanisms of SCZ by integrating genome-wide association study (GWAS) data from European (N = 130,644) and East Asian (N = 30,761) population, alongside multi-omics and single-cell sequencing analyses. Cross-method validation identified seven core genes (e.g., MDK, RERE, ERBB4), with RERE exhibiting a notably high eQTL-SCZ colocalization probability of 92.8-93.9%. Single-cell and epigenetic analyses reveal that the spatiotemporal dynamics of RERE may lead to differences in its mediated SCZ disease risk at the levels of genetic variation and transcriptional regulation. Cleavage Under Targets and Tagmentation (CUT&Tag) confirmed that RERE directly regulates synaptic genes such as PPP4R3B and RPS27L, and its co-expression network was found to be strongly linked to SCZ risk. This study unveils a RERE-mediated epigenetic-neurodevelopmental axis and suggests that GABAergic neurons may be a potential new target for the treatment of SCZ. Future validation using organoid models and exploration of clinical translation are warranted.