The <em>NCAN</em> gene: schizophrenia susceptibility and cognitive dysfunction

Abstract

BackgroundCognitive dysfunction has been recognized as a cardinal feature of schizophrenia. Elucidating the neurobiological substrates of cognitive dysfunction in schizophrenia would help identify the underlying mechanism of this disorder. The rs1064395 single nucleotide polymorphism, within the gene encoding neurocan (NCAN), is reported to be associated with schizophrenia in European populations and may influence brain structure in patients with schizophrenia.MethodsIn this study, we aimed to explore whether NCAN rs1064395 confers some risk for schizophrenia and cognitive dysfunction in Han Chinese. We recruited 681 patients with schizophrenia and 699 healthy subjects. Two hundred and fifty-four patients were evaluated according to Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).ResultsThere were no significant differences in genotype or allele distributions of the rs1064395 polymorphism between the schizophrenia and control groups. Patients showed significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory, and total RBANS score. Patients with the A/A or A/G genotype of rs1064395 had lower scores of immediate memory, visuospatial skill, attention, and total RBANS score than those with the G/G genotype. We performed an expression quantitative trait loci analysis and observed a significant association between rs1064395 and NCAN expression in the frontal (P=0.0022, P=0.022 after Bonferroni correction) and cerebellar cortex (P=0.0032, P=0.032 after Bonferroni correction).ConclusionOur findings indicate that this single nucleotide polymorphism may be a risk factor for cognitive dysfunction in patients with schizophrenia. Further investigations are warranted for validation purposes and to identify the precise mechanism by which rs1064395 influences cognitive performance in patients with schizophrenia.

Further Evidence of an Association between <b><i>NCAN</i></b> rs1064395 and Bipolar Disorder

“…Although the precise function of this SNP remains unclear, as it locates in the 3′ untranslated region of the NCAN gene, previous studies have implicated its regulative effects on the mRNA expression of NCAN in the frontal and cerebellar cortex [27]. As stated in a previous study [28], NCAN preferentially affected mania symptoms in humans, and homozygous Ncan knockout mice showed behavioral abnormal­ities that were strikingly similar to those of the human mania phenotype; neurobiological studies from this perspective are necessary.…”

“…However, this SNP did not reach genome-wide significance in other BPD GWAS [15, 17-19], which may be the result of genetic background heterogeneity among different samples. However, a potential impact of rs1064395 on the risk of BPD was supported by its associations with brain function, cognitive performance, and risk of other psychiatric disorder (i.e., schizophrenia) [23-27]. In addition, a previous study found that the rs1064395 risk allele was significantly associated with the “mania” factor, which was confirmed by the discovery that compared to wild-type mice, the homozygous Ncan knockout mice were more hyperactive and exhibited more frequent risk-taking and repetitive behaviors, less depression-like conduct, plus impaired prepulse inhibition, amphetamine hypersensitivity, as well as increased saccharin preference [28].…”

Neurocan Inhibits Semaphorin 3F Induced Dendritic Spine Remodeling Through NrCAM in Cortical Neurons

“…The involvement of Neurocan in regulating synapse remodeling on both excitatory and inhibitory neurons makes it an important candidate molecule for neurodevelopmental disorders with aberrant spine and synapse numbers that could impact cortical excitatory/inhibitory balance. In schizophrenia, PNNs are notably altered in human prefrontal cortex ( Berretta et al, 2015 ) where dendritic spine density is markedly diminished ( Garey et al, 1998 ; Glausier and Lewis, 2013 ; Moyer et al, 2015 ; MacDonald et al, 2017 ), and Neurocan is a candidate locus for schizophrenia, bipolar, and other neurological disorders ( Cichon et al, 2011 ; Muhleisen et al, 2012 ; Schultz et al, 2014 ; Wang et al, 2016 ).…”

“…Neurocan is a CSPG that is a prominent organizer of PNNs in the neocortex. Genetic studies in humans have identified Neurocan as a potential risk factor for schizophrenia, bipolar disorder ( Muhleisen et al, 2012 ; Schultz et al, 2014 ; Wang et al, 2016 ), and dyslexia ( Einarsdottir et al, 2017 ). Our interest in mechanisms regulating spine density in the developing cortex led us to investigate molecules that may mediate the reduction of spine remodeling that occurs with maturation.…”

Genetic association analysis of microRNA137 and its target complex 1 with schizophrenia in Han Chinese

“…Animal experiment showed that CPLX1 knockout mice have pronounced deficits in social behaviors 31 . It is known that schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms and its etiological heterogeneity is manifested 32 – 35 . Therefore, although no association of CPLX1 with schizophrenia susceptibility was observed in our samples, we could not fully exclude the possible involvement of CPLX1 in the development of cognitive dysfunction in schizophrenia.…”