Towards understanding the schizophrenia code: An expanded convergent functional genomics approach

Abstract

Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder.

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

“…[1][2][3] In search of promising candidate genes, studies of gene expression in brain samples from patients with schizophrenia or various cellular and animal models have also been carried out. 4 Using such a functional convergent genomics approach, we investigated transcriptional responses in cultured human glial cells exposed to antipsychotic drugs. We found that some typical and atypical antipsychotics markedly upregulated several genes involved in the biosynthesis of cholesterol and fatty acids.…”

Convergent Functional Genomics: what we have learned and can learn about genes, pathways, and mechanisms

“…This approach has been applied, among others, to the study of bipolar disorder (Le-Niculescu et al, 2009b;Niculescu et al, 2000;Ogden et al, 2004) and schizophrenia (Le-Niculescu et al, 2007), as well as to the identification of blood biomarkers (Le-Niculescu et al, 2009a). Human data increase the relevance to the disorder (specificity), whereas animal model data increase the ability to identify the signal (sensitivity).…”

No association between the oligodendrocyte-related gene PLP1 and schizophrenia in the Japanese population

“…In light of the fact that a large body of expression-based studies have shown significantly lower levels of PLP1 mRNA transcripts in animal models of schizophrenia or in brain tissue from deceased schizophrenic patients in comparison with healthy controls (Tkachev et al 2003;Aston et al 2004;Le-Niculescu et al 2007), our results suggest that the downregulation is not influenced by the predisposing common genetic variants within or in close vicinity to the PLP1 gene region.…”

“…An emerging body of work over the last 5 years has implicated myelin/glia related dysfunction in schizophrenia (Tkachev et al 2003;Aston et al 2004;Le-Niculescu et al 2007). Moreover, downregulation of at least some of the many abnormally expressed myelin-associated genes in schizophrenia might be influenced by a systematic mechanism such as methylation, as in case of SOX10 (Iwamoto et al 2005), or a transcriptional factor that can exert an effect on multiple myelin-associated genes such as QKI (Aberg et al 2006;Haroutunian et al 2006) rather than an SNP in the regulatory region of each abnormally expressed myelin-associated genes.…”

“…A large number of expression-and animal-model-based studies have shown significantly lower levels of PLP1 messenger ribonucleic acid (mRNA) in schizophrenia (Tkachev et al 2003;Aston et al 2004;Le-Niculescu et al 2007;Sokolov 2007). One study examined the hypothesis of PLP1 as candidate gene (Qin et al 2005), and data provided evidence for genetic association with schizophrenia.…”