Abstract
Schizophrenia (SCZ) is a psychiatric disorder of unknown etiology. There is evidence suggesting that aberrations in neurodevelopment are a significant attribute of schizophrenia pathogenesis and progression. To identify biologically relevant molecular abnormalities affecting neurodevelopment in SCZ we used cultured neural progenitor cells derived from olfactory neuroepithelium (CNON cells). Here, we tested the hypothesis that variance in gene expression differs between individuals from SCZ and control groups. In CNON cells, variance in gene expression was significantly higher in SCZ samples in comparison with control samples. Variance in gene expression was enriched in five molecular pathways: serine biosynthesis, PI3K-Akt, MAPK, neurotrophin and focal adhesion. More than 14% of variance in disease status was explained within the logistic regression model (C-value = 0.70) by predictors accounting for gene expression in 69 genes from these five pathways. Structural equation modeling (SEM) was applied to explore how the structure of these five pathways was altered between SCZ patients and controls. Four out of five pathways showed differences in the estimated relationships among genes: between KRAS and NF1, and KRAS and SOS1 in the MAPK pathway; between PSPH and SHMT2 in serine biosynthesis; between AKT3 and TSC2 in the PI3K-Akt signaling pathway; and between CRK and RAPGEF1 in the focal adhesion pathway. Our analysis provides evidence that variance in gene expression is an important characteristic of SCZ, and SEM is a promising method for uncovering altered relationships between specific genes thus suggesting affected gene regulation associated with the disease. We identified altered gene-gene interactions in pathways enriched for genes with increased variance in expression in SCZ. These pathways and loci were previously implicated in SCZ, providing further support for the hypothesis that gene expression variance plays important role in the etiology of SCZ.
Highlights
Schizophrenia (SCZ) is a psychiatric disorder with high heritability; estimates from twin and family-based studies suggest that the heritability of SCZ may be as high as 81% (Cardno and Gottesman, 2000; Sullivan et al, 2003; Lichtenstein et al, 2009; Wray and Gottesman, 2012)
In addition to pathways enriched in differentially expressed genes (Wnt, Notch, Serine biosynthesis; Evgrafov et al, 2017), we found that PI3K-Akt signaling has been identified as important in multiple studies of SCZ (Mao et al, 2009; Panaccione et al, 2013; Singh et al, 2013; Topol et al, 2015; Mulligan and Cheyette, 2016; Howell et al, 2017; Wang et al, 2017)
These two sets were merged into one set of five unique pathways for further analysis—serine biosynthesis, PI3K-Akt, MAPK, neurotrophin signaling and focal adhesion (Table 1)
Summary
Schizophrenia (SCZ) is a psychiatric disorder with high heritability; estimates from twin and family-based studies suggest that the heritability of SCZ may be as high as 81% (Cardno and Gottesman, 2000; Sullivan et al, 2003; Lichtenstein et al, 2009; Wray and Gottesman, 2012). While the estimated heritability of SCZ is high, the proportion explained by SNPs is smaller, with the genetic liability explained by SNPs estimated to be between 20%–35% when considering SNPs genome-wide (Lee et al, 2012; Cross-Disorder Group of the Psychiatric Genomics Consortium et al, 2013; Speed et al, 2017), or 3.4% when considering only SNPs with genome-wide significance in SCZ GWAS (Schizophrenia Working Group of the Psychiatric Genomics Consortium et al, 2014). If SCZ is a disorder of pathways (Sullivan, 2012) GWAS alone is unlikely to offer immediate insight into the molecular basis of SCZ
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