Expression of DISC1-Interactome Members Correlates with Cognitive Phenotypes Related to Schizophrenia

Abstract

Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.

DISC1 gene and affective psychopathology: A combined structural and functional MRI study

“…Third, the DISC1-gene is a complex because there are haplotypes on this gene, including the Ser704Cys SNP, influencing brain structure and activation during memory and executive processing (Callicott et al, 2005;Palo et al, 2007). In addition, DISC1 interacts with other proteins and therefore other genes influence the effects of the DISC1-gene on cognitive functioning (Duff et al, 2013;Rampino et al, 2014). These effects could pose challenges to accurately model the effect of the Ser704Cys SNP.…”

Expression Alteration of Disrupted in Schizophrenia 1 (DISC1) Gene, a Potential Peripheral Marker for Schizophrenia and Paranoid Personality Disorder

“…DISC1 was co segregates with major psychiatric illness in a great Scottish pedigree, Finnish cohort and Taiwanese families [4]. The DISC1 protein in interaction with number of proteins regulates several cellular functions and molecular pathways, including neuronal migration (LIS1, NDE1, NDEL1, Dixdc1), axonal bundling and elongation (FEZ1), neural progenitor proliferation (GSK3β), cell cycle regulation (PCM1), neuronal signaling (Girdin, GSK3β, PDE4), and signal transduction (Kal7, TNIK, AKAP9) [7]. Mouse models indicate the role of DISC1 protein in neurodevelopment of several brain regions, such as olfactory bulb, cortex, hippocampus, hypothalamus, cerebellum and brain stem and morphological development of adult-born granule neurons [4,8].…”

“…Mouse models indicate the role of DISC1 protein in neurodevelopment of several brain regions, such as olfactory bulb, cortex, hippocampus, hypothalamus, cerebellum and brain stem and morphological development of adult-born granule neurons [4,8]. In human peripheral blood few studies were conducted and down expression of DISC1 genes and some of the DISC1-interactome genes such as NDEL1 has been reported in schizophrenic subjects compared to non-psychiatric controls [7]. Cytoarchitectual alteration in the hippocampus is a neuropathological marker for schizophrenia.…”

Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31

“…This rare variant shows significant co-segregation with schizophrenia, bipolar disorder and depression in a large family [16]. Recent studies have also shown that variation is DISC1 is also associated with other psychiatric phenotypes such as cognitive dysfunction and drug abuse [17,18,19,20]. Findings of linkage from individual pedigrees are few.…”