Unraveling the Role of De Novo Structural Variants in Schizophrenia using Long-read Sequencing

Genetic liability to schizophrenia spans diverse mutations, yet structural variations (SVs) remain underexplored. Here, we utilized short-read sequencing (SRS) and long-read sequencing (LRS) in schizophrenia trios to investigate de novo SVs (dnSVs). Employing a high-accuracy pipeline, we validated 11 dnSVs, including four dnSVs located in conserved gene coding regions. Integrating our findings with prior de novo mutation (DNM) identified JARID2, XPO7, and ZNF420 with a statistically higher burden of lost-of-function DNMs. Genes harboring damaging DNMs in this study interacted closely with established schizophrenia-susceptible genes. Notably, potentially clinically relevant variants were identified in 5 of 38 probands (13.2%). Functional experiments demonstrated that the 11.1 kb deletion in PPP3CA reduced its expression and hippocampal knockdown in mice induced schizophrenia-like behaviors. Mass spectrometry analysis uncovered altered phosphorylation in glutamatergic and GABAergic synapses, implicating excitation-inhibition balance. These findings underscore the value of incorporating LRS to fully characterize the genetic architecture of schizophrenia.We have uploaded the source data and the custom Python scripts associated with this study. All additional bioinformatics software, parameters, and analysis results are provided in the Materials and Methods section and the Supplementary Information.