A genome-wide supported psychiatric risk variant in<i>NCAN</i>influences brain function and cognitive performance in healthy subjects

Raum, Heidelore; Dietsche, Bruno; Nagels, Arne; Witt, Stephanie H.; Rietschel, Marcella; Kircher, Tilo; Krug, Axel

doi:10.1002/hbm.22635

Cited by 27 publications

(33 citation statements)

References 84 publications

(158 reference statements)

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“…The results agree well with a recent study (Raum et al, 2015), showing that NCAN rs1064395 A-carriers have significant deficits in memory tasks associated with hippocampal function compared with GG homozygotes, and show differences in brain activation in temporal areas, which were also affected by genotype in our healthy sample. Conversely, different results were obtained in a study by Schultz et al, who reported NCAN genotype effects on cortical folding only in schizophrenia patients but not in healthy controls.…”

Section: Discussionsupporting

confidence: 93%

NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression

Dannlowski

Kugel

Grotegerd

et al. 2015

Neuropsychopharmacol

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Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors.

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Section: Discussionsupporting

confidence: 93%

NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression

Dannlowski

Kugel

Grotegerd

et al. 2015

Neuropsychopharmacol

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“…In this study, we found that schizophrenic patients with the A allele of NCAN rs1064395 have poorer cognitive processes, such as immediate memory, visuospatial skill, and attention, compared with those without the A allele. This result is in agreement with a recent study reporting that rs1064395A allele carriers exhibit poorer immediate and delayed verbal memory performance than those with the G/G genotype, implying that this SNP influences both neural processing and cognitive performance 33. We then carried out an eQTL analysis and found that rs1064395 is significantly associated with NCAN expression in the frontal and cerebellar cortex.…”

Section: Discussionsupporting

confidence: 92%

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

Wang

Cai

et al. 2016

NDT

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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.

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“…This accentuated phenotype begs the question as to whether a significant change of hippocampal activity could also prevail on the system physiology level that would offer new insight into the role of perineuronal nets for synaptic plasticity and synaptic information storage in the adult animal. Insights of this kind are particularly relevant, given recent reports for a role of perineuronal net disruption in schizophrenia (Schultz et al, ; Berretta, Pantazopoulos, Markota, Brown, & Batzianouli, ; Raum et al, ) and bipolar disorder (Miró et al, ; Mühleisen et al, ; Schultz et al, ; Raum et al, ).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic cellular and molecular properties of in vivo hippocampal synaptic plasticity are altered in the absence of key synaptic matrix molecules

et al. 2017

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Hippocampal synaptic plasticity comprises a key cellular mechanism for information storage. In the hippocampus, both long-term potentiation (LTP) and long-term depression (LTD) are triggered by synaptic Ca -elevations that are typically mediated by the opening of voltage-gated cation channels, such as N-methyl-d-aspartate receptors (NMDAR), in the postsynaptic density. The integrity of the post-synaptic density is ensured by the extracellular matrix (ECM). Here, we explored whether synaptic plasticity is affected in adult behaving mice that lack the ECM proteins brevican, neurocan, tenascin-C, and tenascin-R (KO). We observed that the profiles of synaptic potentiation and depression in the dentate gyrus (DG) were profoundly altered compared to plasticity profiles in wild-type littermates (WT). Specifically, synaptic depression was amplified in a frequency-dependent manner and although late-LTP (>24 hr) was expressed following strong afferent tetanization, the early component of LTP (<75 min post-tetanization) was absent. LTP (>4 hr) elicited by weaker tetanization was equivalent in WT and KO animals. Furthermore, this latter form of LTP was NMDAR-dependent in WT but not KO mice. Scrutiny of DG receptor expression revealed significantly lower levels of both the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor, of the metabotropic glutamate receptor, mGlu5 and of the L-type calcium channel, Ca 1.3 in KO compared to WT animals. Homer 1a and of the P/Q-type calcium channel, Ca 1.2 were unchanged in KO mice. Taken together, findings suggest that in mice that lack multiple ECM proteins, synaptic plasticity is intact, but is fundamentally different.

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A genome-wide supported psychiatric risk variant inNCANinfluences brain function and cognitive performance in healthy subjects

Cited by 27 publications

References 84 publications

NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression

NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression

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

Intrinsic cellular and molecular properties of in vivo hippocampal synaptic plasticity are altered in the absence of key synaptic matrix molecules

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