This research conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. Transcriptome from these cells was obtained using Illumina HiSeq 2500, and differential expression analyses were performed using DESeq2 (|fold change|>1.5 and false discovery rate < 0.3), in patients compared to controls. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology. Researchers identified 454 differentially expressed genes in hiPSC-derived neurons, enriched in pathways including phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3) signaling, with serum-glucocorticoid kinase 1 (SGK1), an inhibitor of glycogen synthase kinase 3β, as part of this pathway. While demonstrating the utility of hiPSCs derived from multiplex families to identify significant cell-specific gene network alterations in SCZ, these studies support a role for disruption of PI3K/GSK3 signaling as a risk factor for SCZ. The functional significance of potential SCZ susceptibility loci [1] can be assessed using hiPSC technology.
The population of the Central Valley of Costa Rica (CVCR) is considered a genetically homogeneous population. Therefore for this study, they performed in-depth genetic studies of SCZ families from the CVCR and have identified several potential SCZ candidate genes. Among the DEGs in the PI3K/GSK3 signaling pathway was serum-glucocorticoid kinase 1 (SGK1), an inhibitor of glycogen synthase kinase 3β (GSK3β) [16,17,18], which has been implicated in SCZ and in neuronal morphogenesis.
This study is the first to identify PI3K/GSK3 signaling alterations in SCZ neurons. Overall, our results highlight that transcriptomic alterations in SCZ patients are cell type specific and demonstrate the potential of hiPSCs derived from subjects with a common genetic background to identify gene networks and signaling alterations that may underlie the molecular and cellular mechanisms in SCZ.
Ref: https://www.nature.com/articles/s41386-020-00924-0
