Co-expression network analysis from genes involved with neural-differentiation shows specific pattern in patients with schizophrenia

Schizophrenia is a severe and debilitating neuropsychiatric disorder with the involvement of genetic and environmental factors contributing to its pathogenesis. The specific role of the brain cell types in the disease remains uncovered due to the difficulties in accessing diseased tissue. This study analysed molecular alterations in human induced pluripotent stem cells (hiPSCs) derived from fibroblasts from control subject and individual with schizophrenia and further differentiated to neuron to identify genes relevant for the development of schizophrenia. We identified 228 genes that are involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. These genes were analysed in expression microarrays of post-mortem brain tissue (frontal cortex) of additional patients with schizophrenia and normal individuals revealing only six common genes: CACNA1E, CEBPB, DUX4, EDNRA, SPHK1 and SPRY4 (GSE62191). Furthermore, a co-expression network analysis of the 228 genes revealed a non-conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation as involved with schizophrenia. This study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain. Biopsies of primary human fibroblasts from a 48-year-old woman with DSM-IVTR schizophrenia defined as treatment-resistant under clozapine treatment (SZCP) were collected in parallel with a control subject (CON) negative for any major lifetime DSM-IVTR diagnosis. Fibroblasts underwent primary culture procedures to generate hiPSCs and were subsequently differentiated into neuron precursor cells (NPCs). Samples generation and culture conditions are described in Paulsen et al. (2011). Five replicates of expression microarray experiments using a reference design, where test sample (NPC) is derived from reference sample (hiPSC).