F178. Transcriptome profiling in hiPSC-derived cell lines from schizophrenia subjects identifies neuron-specific alterations in expression of extracellular matrix genes

Abstract

Background. Human induced pluripotent stem cells (hiPSC) have revolutionized the study of the biological mechanisms of schizophrenia (SCZ) and other psychiatric disorders as they allow for the establishment of brain cellular models that account for a patient’s genetic background. Here we conducted an RNA-sequencing profiling study of cell lines derived from hiPSCs generated from lymphoblastoid cell lines (LCL) of subjects, including a multiplex family, from the population isolate of the Central Valley of Costa Rica (CVCR). Methods. LCLs, hiPSCs, neural precursor cells (NPCs), cortical neurons, and astrocytes derived from 6 healthy controls and 7 SCZ subjects were generated using standard methodology. RNA from these cells was sequenced using Illumina HiSeqTM2500. Cell composition analysis was performed by CIBERSORT. Normalization and differential expression (DE) analysis were performed using DESeq2 (FC > 1.5 or <0.067 and FDR < 0.3) in patients compared to controls in each brain cell type. Gene set enrichment analysis was performed using DAVID 6.8. Results. HiPSC-derived neurons were responsible for 94.4% of the variance seen on DE analyses, where 454 differentially expressed genes (DEGs) were identified in neurons. Neuronal DEGs were enriched in pathways related to extracellular matrix organization and system development, further supporting a role for alterations in extracellular matrix proteins and impairments in synapse formation during brain development as an underlying mechanism in SCZ. Conclusions. Our results highlight the importance of cell type when studying molecular alterations underlying SCZ and demonstrate the utility of hiPSC cells derived from multiplex families to identify specific and significant gene network alterations in SCZ.