Unraveling schizophrenia's genetic complexity through advanced causal inference and chromatin 3D conformation

Abstract

Schizophrenia is a polygenic complex disease with a heritability as high as 80 %, yet the mechanism of polygenic interaction in its pathogenesis remains unclear. Studying the interaction and regulation of schizophrenia susceptibility genes is crucial for unraveling the pathogenesis of schizophrenia and developing antipsychotic drugs. Therefore, we developed a bioinformatics method named GRACI (Gene Regulation Analysis based on Causal Inference) based on the principles of information theory, a causal inference model, and high order chromatin 3D conformation. GRACI captures the interaction and regulatory relationships between schizophrenia susceptibility genes by analyzing genotyping data. Two datasets, comprising 1459 and 2065 samples respectively, were analyzed, and the gene networks from both datasets were constructed. GRACI showcased superior accuracy when compared to widely adopted methods for detecting gene-gene interactions and intergenic regulation. This alignment was further substantiated by its correlation with chromatin high-order conformation patterns. Using GRACI, we identified three potential genes—KCNN3, KCNH1, and KCND3—that are directly associated with schizophrenia pathogenesis. Furthermore, the results of GRACI on the standalone dataset illustrated the method's applicability to other complex diseases. GRACI download: https://github.com/liuliangjie19/GRACI