Unravelling genes and pathways implicated in working memory of schizophrenia in Han Chinese.
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ABSTRACT:
SUBMITTER: Ren H
PROVIDER: S-EPMC4307354 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
Publications
Unravelling genes and pathways implicated in working memory of schizophrenia in Han Chinese.
Ren Hongyan H Zhang Chengcheng C Huang Chaohua C Li Na N Li Mingli M Li Yinfei Y Deng Wei W Ma Xiaohong X Xiang Bo B Wang Qiang Q Li Tao T
International journal of molecular sciences 20150120 1
Working memory deficit is the core neurocognitive disorder in schizophrenia patients. To identify the factors underlying working memory deficit in schizophrenia patients and to explore the implication of possible genes in the working memory using genome-wide association study (GWAS) of schizophrenia, computerized delay-matching-to-sample (DMS) and whole genome genotyping data were obtained from 100 first-episode, treatment-naïve patients with schizophrenia and 140 healthy controls from the Menta ...[more]
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Project description:AimsThe dopamine- and cAMP-regulated phosphoprotein (DARPP-32), which is encoded by the PPP1R1B gene, plays a converging regulatory role in the central nervous system by mediating the actions of dopamine, serotonin, and glutamate. Previous studies have demonstrated that variations in genes related to the dopamine system influence working memory. The present study thus investigated whether polymorphisms in PPP1R1B gene were associated with working memory.Materials and methodsA sample of 124 healthy Han Chinese were genotyped for three single nucleotide polymorphisms of PPP1R1B gene, namely rs12601930C/T, rs879606A/G, and rs3764352A/G, using polymerase chain reaction and restriction fragment length polymorphism analysis. Working memory performance was assessed using the Wisconsin Card Sorting Test (WCST).ResultsSignificant differences were observed in the Total Correct (TC), Total Errors (TE), and Conceptual Level Responses (CLR) scores of the WCST among the three rs12601930C/T genotypes (p = 0.044, 0.044, and 0.047, respectively); in TC, TE, Non-Perseverative Errors (NPE), and CLR scores between participants with the CC and (CT + TT) rs12601930C/T polymorphism genotypes (p = 0.032, 0.032, 0.019, and 0.029, respectively); in TC, TE, Perseverative Errors (PE), NPE, and CLR scores between participants with the (CT + CC) and TT rs12601930C/T polymorphism genotypes (p = 0.001, 0.001, 0.011, 0.004, and 0.001, respectively); and in NPE and CLR scores between participants with the GG and (AG + AA) genotypes of the rs3764352A/G polymorphism (p = 0.011 and 0.010). Furthermore, for males only, there were significant differences in TC, TE, PE, NPE, and CLR scores among the rs12601930C/T genotypes (p = 0.020, 0.020, 0.037, 0.029, and 0.014, respectively) and NPE and CLR scores among the rs3764352 genotypes (p = 0.045 and 0.042).ConclusionPPP1R1B gene polymorphisms rs12601930C/T and rs3764352A/G might be associated with working memory assessed by the WCST in healthy Chinese adults, especially among males.
| S-EPMC9685989 | biostudies-literature
Project description:Schizophrenia (SCZ) is a severe psychiatric disorder affecting 0.7% of the population.[1] When inadequately treated, subjects with SCZ experience symptoms that render them dysfunctional and unable to discern aspects of reality. Despite the fact that the majority of subjects with SCZ are sporadic cases and do not have a known family history of SCZ, a family history is one of the largest risk factors for developing SCZ.[2-4] A large genome-wide association study (GWAS) recently pinpointed 108 significant loci within the human genome that contribute to SCZ pathogenesis.[5] While some loci include genes that have been previously implicated in SCZ, the majority, due to the unbiased nature of the genetic investigation, include genes with unknown relevance to SCZ. This investigation is based on the premise that: 1) at least one of the genes at the 108 loci contribute to SCZ etiology; 2) some of the genes contributing to SCZ etiology are in a common pathway; and 3) some genes in a common pathway will have correlated gene expression. Gene expression data available in the gene expression omnibus (GEO) was used to identify correlated expression among the 369 genes (853 isoforms) found at the 108 loci associated with SCZ. Expression data came from bone marrow CD34+ selected cells isolated from 66 individuals (GSE4619). First, correlation among genes related to the DRD2 pathway was analyzed to test the hypothesis that some SCZ genes are in a common pathway and have correlated expression. Then, two pathways were generated based on correlated expression of genes at the 108 loci. One pathway consisted of the largest number of genes with correlated expression (56) and included four genes from the DRD2 pathway and seven of the 33 genes that were previously implicated in SCZ. The second pathway, a novel pathway of 12 genes, was constructed by excluding both the 33 genes that were previously implicated in SCZ and other genes that exhibited significantly correlated expression with these 33 genes. Correlated expression analysis among SCZ-associated genes at the 108 loci provides evidence implicating those genes with correlated expression in SCZ pathogenesis. In addition, these analyses will facilitate pathway identification creating starting points for targeted experiments to verify or refute the hypothetical pathways generated here. Ultimately identifying the genes and pathways at the 108 loci involved in SCZ genesis will inform novel pharmaceutical development for treatment and prevention of SCZ.
| S-EPMC7454191 | biostudies-literature
Project description:BACKGROUND: Monoamine oxidases (MAOs) catalyze the metabolism of dopaminergic neurotransmitters. Polymorphisms of isoforms MAOA and MAOB have been implicated in the etiology of mental disorders such as schizophrenia. Association studies detected these polymorphisms in several populations, however the data have not been conclusive to date. Here, we investigated the association of MAOA and MAOB polymorphisms with schizophrenia in a Han Chinese population. METHODS: Two functional single nucleotide polymorphisms (SNPs), rs6323 of MAOA and rs1799836 of MAOB, were selected for association analysis in 537 unrelated schizophrenia patients and 536 healthy controls. Single-locus and Haplotype associations were calculated. RESULTS: No differences were found in the allelic distribution of rs6323. The G allele of rs1799836 was identified as a risk factor in the development of schizophrenia (P = 0.00001). The risk haplotype rs6323T-rs1799836G was associated with schizophrenia in female patients (P = 0.0002), but the frequency difference was not significant among male groups. CONCLUSIONS: Our results suggest that MAOB is a susceptibility gene for schizophrenia. In contrast, no significant associations were observed for the MAOA functional polymorphism with schizophrenia in Han Chinese. These data support further investigation of the role of MAO genes in schizophrenia.
| S-EPMC3201892 | biostudies-literature
Project description:People with schizophrenia (PSZ) exhibit signs of reduced working memory (WM) capacity. However, this may reflect an impairment in managing its content, e.g. preventing irrelevant information from taking up available storage space, rather than a true capacity reduction. We tested the ability to eliminate and update WM content in 38 PSZ and 30 healthy control subjects (HCS). Images of real-world objects were presented consecutively, and a tone cued the item most likely to be tested for memory. On half the trials, randomly intermixed, a second tone occurred. Participants were informed that the item cued by the second tone was now the most likely to be tested, and the item cued by the first tone now the least likely, providing incentive to eliminate the first cued item from WM. Both HCS and PSZ displayed a robust performance advantage for cued items. Unexpectedly, PSZ more efficiently removed the no-longer-essential item from WM than HCS. The magnitude of the WM clearance of this first cued item correlated with memory performance for the newly prioritized second cued item in PSZ, indicating that it was adaptive. However, WM clearance was not associated with WM capacity, ruling out the need to budget limited resources as an explanation for greater clearance in PSZ. A robust correlation between WM clearance and poverty of speech in PSZ instead suggests that the propensity to rapidly clear non-essential information and minimize the number of items in WM may be the reflection of a negative symptom trait. This finding may reflect a more general tendency of PSZ to focus processing more narrowly than HCS.
| S-EPMC3275350 | biostudies-literature
Project description:The neural correlates of working memory (WM) impairment in schizophrenia remain a key puzzle in understanding the cognitive deficits and dysfunction of dorsolateral prefrontal cortex observed in this disorder. We sought to determine whether patients with schizophrenia exhibit an alteration in the inverted-U relationship between WM load and activation that we recently observed in healthy individuals and whether this could account for WM deficits in this population.Medicated (n = 30) and unmedicated (n = 21) patients with schizophrenia and healthy control subjects (n = 45) performed the self-ordered WM task during functional magnetic resonance imaging. We identified regions exhibiting an altered fit to an inverted-U relationship between WM load and activation that were also predictive of WM performance.A blunted inverted-U response was observed in left dorsolateral prefrontal cortex in patients and was associated with behavioral deficits in WM capacity. In addition, suppression of medial prefrontal cortex during WM was reduced in patients and was associated with poorer WM capacity in patients. Finally, activation of visual cortex in the cuneus was elevated in patients and associated with improved WM capacity. Together, these findings explained 55% of the interindividual variance in WM capacity when combined with diagnostic and medication status, which alone accounted for only 22% of the variance in WM capacity.These findings identify a novel biomarker and putative mechanism of WM deficits in patients with schizophrenia, a reduction or flattening of the inverted-U relationship between activation and WM load observed in healthy individuals in left dorsolateral prefrontal cortex.
| S-EPMC4995154 | biostudies-literature
Project description:Computational neuroscience models propose that working memory (WM) involves recurrent excitatory feedback loops that maintain firing over time along with lateral inhibition that prevents the spreading of activity to other feature values. In behavioral paradigms, this lateral inhibition appears to cause a repulsion of WM representations away from each other and from other strong sources of input. Recent computational models of schizophrenia have proposed that reduction in the strength of inhibition relative to strength of excitation may underlie impaired cognition, and this leads to the prediction that repulsion effects should be reduced in people with schizophrenia spectrum disorders (PSZ) relative to healthy control subjects (HCS). We tested this hypothesis in 2 experiments measuring WM repulsion effects. In Experiment 1, 45 PSZ and 32 HCS remembered the location of a single object relative to a centrally presented visual landmark and reported this location after a short delay. The reported location was repelled away from the landmark in both groups, but this repulsion effect was increased rather than decreased in PSZ relative to HCS. In Experiment 2, 41 PSZ and 34 HCS remembered 2 sequentially presented orientations and reported each orientation after a short delay. The reported orientations were biased away from each other in both groups, and this repulsion effect was again more pronounced in PSZ than in HCS. Contrary to the widespread hypothesis of reduced inhibition in schizophrenia, we provide robust evidence from 2 experiments showing that the behavioral performance of PSZ exhibited an exaggeration rather than a reduction of competitive inhibition. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
| S-EPMC7606631 | biostudies-literature
Project description:Research on emotional processing in schizophrenia suggests relatively intact subjective responses to affective stimuli "in the moment." However, neuroimaging evidence suggests diminished activation in brain regions associated with emotional processing in schizophrenia. We asked whether given a more vulnerable cognitive system in schizophrenia, individuals with this disorder would show increased or decreased modulation of working memory (WM) as a function of the emotional content of stimuli compared with healthy control subjects. In addition, we examined whether higher anhedonia levels were associated with a diminished impact of emotion on behavioral and brain activation responses. In the present study, 38 individuals with schizophrenia and 32 healthy individuals completed blocks of a 2-back WM task in a functional magnetic resonance imaging scanning session. Blocks contained faces displaying either only neutral stimuli or neutral and emotional stimuli (happy or fearful faces), randomly intermixed and occurring both as targets and non-targets. Both groups showed higher accuracy but slower reaction time for negative compared to neutral stimuli. Individuals with schizophrenia showed intact amygdala activity in response to emotionally evocative stimuli, but demonstrated altered dorsolateral prefrontal cortex (DLPFC) and hippocampal activity while performing an emotionally loaded WM-task. Higher levels of social anhedonia were associated with diminished amygdala responses to emotional stimuli and increased DLPFC activity in individuals with schizophrenia. Emotional arousal may challenge dorsal-frontal control systems, which may have both beneficial and detrimental influences. Our findings suggest that disturbances in emotional processing in schizophrenia relate to alterations in emotion-cognition interactions rather than to the perception and subjective experience of emotion per se.
| S-EPMC3160211 | biostudies-other
Project description:Reward processing and cognition are disrupted in schizophrenia (SCZ), yet how these processes interface is unknown. In SCZ, deficits in reward representation may affect motivated, goal-directed behaviors. To test this, we examined the effects of monetary reward on spatial working memory (WM) performance in patients with SCZ. To capture complimentary effects, we tested biophysically grounded computational models of neuropharmacologic manipulations onto a canonical fronto-parietal association cortical microcircuit capable of WM computations. Patients with SCZ (n = 33) and healthy control subjects (HCS; n = 32) performed a spatial WM task with 2 reward manipulations: reward cues presented prior to each trial, or contextually prior to a block of trials. WM performance was compared with cortical circuit models of WM subjected to feed-forward glutamatergic excitation, feed-forward GABAergic inhibition, or recurrent modulation strengthening local connections. Results demonstrated that both groups improved WM performance to reward cues presented prior to each trial (HCS d = -0.62; SCZ d = -1.0), with percent improvement correlating with baseline WM performance (r = .472, p < .001). However, rewards presented contextually before a block of trials did not improve WM performance in patients with SCZ (d = 0.01). Modeling simulations achieved improved WM precision through strengthened local connections via neuromodulation, or feed-forward inhibition. Taken together, this work demonstrates that patients with SCZ can improve WM performance to short-term, but not longer-term rewards-thus, motivated behaviors may be limited by strength of reward representation. A potential mechanism for transiently improved WM performance may be strengthening of local fronto-parietal microcircuit connections via neuromodulation or feed-forward inhibitory drive. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
| S-EPMC6197071 | biostudies-literature
Project description:ObjectiveTo better understand the origins of working memory (WM) impairment in schizophrenia we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM task requiring encoding, maintenance, and retrieval/manipulation processes of spatial information.MethodsWe examined time-frequency synchronous energy of cortical source signals that were derived from magnetoencephalography (MEG) localized to cortical regions using WM-related hemodynamic responses and individualized structural head-models.ResultsCompared to thirteen healthy controls (HC), twelve PSZ showed performance deficits regardless of WM-load or duration. During encoding, PSZ had early theta and delta event-related synchrony (ERS) deficits in prefrontal and visual cortices which worsened with greater memory load and predicted WM performance. During prolonged maintenance of material, PSZ showed deficient beta event-related desynchrony (ERD) in dorsolateral prefrontal, posterior parietal, and visual cortices. In retrieval, PSZ showed reduced delta/theta ERS in the anterior prefrontal and ventral visual cortices and diminished gamma ERS in the premotor and posterior parietal cortices.ConclusionsAlthough beta/gamma cortical neural oscillatory deficits for maintenance/retrieval are evident during WM, the abnormal prefrontal theta-frequency ERS for encoding is most predictive of poor WM in schizophrenia.SignificanceTime-frequency-spatial analysis identified process- and frequency-specific neural synchrony abnormalities underlying WM deficits in schizophrenia.
| S-EPMC5745038 | biostudies-literature
Project description:Cognitive impairment, and working memory deficits in particular, are debilitating, treatment-resistant aspects of schizophrenia. Dysfunction of brain network hubs, putatively related to altered neurodevelopment, is thought to underlie the cognitive symptoms associated with this illness. Here, we used weighted degree, a robust graph theory metric representing the number of weighted connections to a node, to quantify centrality in cortical hubs in 29 patients with schizophrenia and 29 age- and gender-matched healthy controls and identify the critical nodes that underlie working memory performance. In both patients and controls, elevated weighted degree in the default mode network (DMN) was generally associated with poorer performance (accuracy and reaction time). Higher degree in the ventral attention network (VAN) nodes in the right superior temporal cortex was associated with better performance (accuracy) in patients. Degree in several prefrontal and parietal areas was associated with cognitive performance only in patients. In regions that are critical for sustained attention, these correlations were primarily driven by between-network connectivity in patients. Moreover, a cross-validated prediction analysis showed that a linear model using a summary degree score can be used to predict an individual's working memory accuracy (r = 0.35). Our results suggest that schizophrenia is associated with dysfunctional hubs in the cortical systems supporting internal and external cognition and highlight the importance of topological network analysis in the search of biomarkers for cognitive deficits in schizophrenia.
| S-EPMC9508261 | biostudies-literature