Functional analysis of schizophrenia genes using GeneAnalytics program and integrated databases

Abstract

Schizophrenia (SCZ) is a chronic debilitating neuropsychiatric disorder with multiple risk factors involving numerous complex genetic influences. We examined and updated a master list of clinically relevant and susceptibility genes associated with SCZ reported in the literature and genomic databases dedicated to gene discovery for characterization of SCZ genes. We used the commercially available GeneAnalytics computer-based gene analysis program and integrated genomic databases to create a molecular profile of the updated list of 608 SCZ genes to model their impact in select categories (tissues and cells, diseases, pathways, biological processes, molecular functions, phenotypes and compounds) using specialized GeneAnalytics algorithms. Genes for schizophrenia were predominantly expressed in the cerebellum, cerebral cortex, medulla oblongata, thalamus and hypothalamus. Psychiatric/behavioral disorders incorporating SCZ genes included ADHD, bipolar disorder, autism spectrum disorder and alcohol dependence as well as cancer, Alzheimer's and Parkinson's disease, sleep disturbances and inflammation. Function based analysis of major biological pathways and mechanisms associated with SCZ genes identified glutaminergic receptors (e.g., GRIA1, GRIN2, GRIK4, GRM5), serotonergic receptors (e.g., HTR2A, HTR2C), GABAergic receptors (e.g., GABRA1, GABRB2), dopaminergic receptors (e.g., DRD1, DRD2), calcium-related channels (e.g., CACNA1H, CACNA1B), solute transporters (e.g., SLC1A1, SLC6A2) and for neurodevelopment (e.g., ADCY1, MEF2C, NOTCH2, SHANK3). Biological mechanisms involving synaptic transmission, regulation of membrane potential and transmembrane ion transport were identified as leading molecular functions associated with SCZ genes. Our approach to interrogate SCZ genes and their interactions at various levels has increased our knowledge and insight into the disease process possibly opening new avenues for therapeutic intervention.

Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder

“…Some other genes known to be linked to psychiatric diseases also exhibited dysregulation in patients with SCZ and BD in our expression profiling studies. For example, the genes NOTCH2, which is a key player in neurodevelopment and SCZ pathogenesis (Sundararajan, Manzardo, & Butler, 2018), and SELENBP1, which exhibits increased expression in the frontal cortex and blood cells in SCZ (Glatt et al, 2005), are also upregulated in SCZ and BD as evident from our microarray analysis. The expression of the glutamate/glucose transporter SLC1A2 (Koeglsperger et al, 2013), which is linked to lithium response in BD, and is associated with the AMPA2 glutamate receptor network in human brain, was also highly upregulated in SCZ, consistent with findings related to prefrontal cortex of SCZ patients (Matute, Melone, Vallejo-Illarramendi, & Conti, 2005).…”

“…For example, the genes NOTCH2, which is a key player in neurodevelopment and SCZ pathogenesis (Sundararajan, Manzardo, & Butler, 2018), and SELENBP1, which exhibits increased expression in the frontal cortex and blood cells in SCZ (Glatt et al, 2005), are also upregulated in SCZ and BD as evident from our microarray analysis. For example, the genes NOTCH2, which is a key player in neurodevelopment and SCZ pathogenesis (Sundararajan, Manzardo, & Butler, 2018), and SELENBP1, which exhibits increased expression in the frontal cortex and blood cells in SCZ (Glatt et al, 2005), are also upregulated in SCZ and BD as evident from our microarray analysis.…”

Identification of Copy Number Variation by Array-CGH in Portuguese Children and Adolescents Diagnosed with Autism Spectrum Disorders

“…Schizophrenia and ASD were reported in cases associated with GRIK4 overexpression and namely in duplications. 21,22 It is suggested an increasing of GRIK4 expression causes a persistent circuit disequilibrium that alters the main amygdala outputs, 23 which might explain the associated disorders, like schizophrenia. Despite that, it is more difficult to understand the pathogenic significance of GRIK4 loss of function.…”

Genetics and Epigenetics of Schizophrenia

“…However, the studies of endophenotypes (characteristics that are intermediate between the genotype and a phenotype of interest) associated with SCZ are not yet enough. Another approach may be the path analysis to identify causal variables that produce phenotypes [21,22]. However, the chosen models of causality are very important [18].…”