Effects of ZNF804A on auditory P300 response in schizophrenia

The common variant rs1344706 within the zinc-finger protein gene ZNF804A has been strongly implicated in schizophrenia (SZ) susceptibility by a series of recent genetic association studies. Although associated with a pattern of altered neural connectivity, evidence that increased risk is mediated by an effect on cognitive deficits associated with the disorder has been equivocal. This study investigated whether the same ZNF804A risk allele was associated with variation in the P300 auditory-evoked response, a cognitively relevant putative endophenotype for SZ. We compared P300 responses in carriers and noncarriers of the ZNF804A risk allele genotype groups in Irish patients and controls (n=97). P300 response was observed to vary according to genotype in this sample, such that risk allele carriers showed relatively higher P300 response compared with noncarriers. This finding accords with behavioural data reported by our group and others. It is also consistent with the idea that ZNF804A may have an impact on cortical efficiency, reflected in the higher levels of activations required to achieve comparable behavioural accuracy on the task used.     

Evidence of IQ-modulated association between ZNF804A gene polymorphism and cognitive function in schizophrenia patients

ZNF804A gene polymorphism rs1344706 has been suggested as the most compelling case of a candidate gene for schizophrenia by a genome-wide association study and several replication studies. The current study of 570 schizophrenia patients and 448 controls again found significantly different genotype frequencies of rs1344706 between patients and controls. More important, we found that this association was modulated by IQ, with a stronger association among individuals with relatively high IQ, which replicated results of Walters et al, 2010. We further examined whether this IQ-modulated association also existed between the SNP and the intermediate phenotypes (working memory and executive functions) of schizophrenia. Data were available from an N-back task (366 patients and 414 controls) and the attention network task (361 patients and 416 controls). We found that the SNP and IQ had significant interaction effects on the intermediate phenotypes for patients, but not for controls. The disease risk allele was associated with poorer cognitive function in patients with high IQ, but better cognitive function in patients with low IQ. Together, these results indicated that IQ may modulate the role of rs1344706 in the etiology of both schizophrenia and its cognitive impairments, and pointed to the necessity of considering general cognitive function as indexed by IQ in the future studies of genetic bases of schizophrenia.     

Further evidence for the association of genetic variants of ZNF804A with schizophrenia and a meta-analysis for genome-wide significance variant rs1344706

Recent accumulating evidence has indicated that ZNF804A (zinc finger protein 804A) may be one of the most robustly implicated genes in schizophrenia. In this report, we examined ZNF804A single nucleotide polymorphisms (SNPs) encompassing exon 4 by performing an association study that used a Han Chinese sample comprised of 492 schizophrenia patients and 516 healthy control subjects. A meta-analysis based on previous studies was also performed. For markers rs4667000 and rs1366842, significant differences in allele frequencies were found between cases and controls (Mantel-Haenszel corrected P=0.014 and P=0.025, respectively). Analysis of haplotype rs61739290-rs1366842 showed significant association with schizophrenia (global P=0.0018). Moreover, several other two-, three-, and four-SNP tests of haplotype association were also significant. A meta-analysis comprised of studies that utilized sample sets of either European and/or Han Chinese origin revealed statistically significant associations for two SNPs (rs1366842, P=0.002; and rs3731834, P=0.03) and schizophrenia. In addition, we observed a significant association between marker rsl344706 and schizophrenia (P<1.0×10(-5)) in combined populations. When we separately analyzed the studies by population, consistent and significant differences were found between cases and controls both in the European samples (P<1.0×10(-4)) and in the Chinese samples (P=0.03). In summary, we have added new evidence supporting the association between ZNF804A and schizophrenia in our Han Chinese sample. Further functional exploration of ZNF804A will greatly help us to elucidate the pathogenesis of schizophrenia and find promising new approaches for the treatment of this disorder.     

Voxel-based analysis of P300 electrophysiological topography associated with positive and negative symptoms of schizophrenia

Abnormal P300 waveforms of the event-related potentials during the auditory oddball task are one of the most consistent findings in patients with schizophrenia. In the present study, we sought to test the hypothesis that the abnormal P300 waveform results from composite representation of neural activity in anatomically distinct brain regions responsible for the manifestation of positive and negative symptoms. We used the low-resolution brain electromagnetic tomography (LORETA) to obtain current density images of the P300 component from 26 patients with schizophrenia. The statistical parametric mapping (SPM) was applied to the LORETA images in order to identify brain regions that are related with the severity of psychotic symptoms as evaluated by the Brief Psychiatric Rating Scale (BPRS). The BPRS Total score was negatively correlated with the P300 current density in the left superior temporal gyrus (r=-0.615, corrected p=0.009) and that in the right medial frontal region (r=-0.571, corrected p=0.019) by means of SPM single-subject covariates model. These brain regions were included in the region-specific P300 sources as represented by the current density maxima (corrected p<0.05) using SPM one-sample t-test. A subsequent region-of-interest analysis of Pearson correlations revealed specific relationships between the Positive subscale score and the mean current density in the left superior temporal gyrus (r=-0.528, p=0.005) and between the Negative subscale score and the mean current densities in the medial frontal region (r=-0.551, p=0.003) and left superior temporal gyrus (r=-0.499, p=0.009). These results indicate that functional disturbances of neural networks involving the medial prefrontal and superior temporal regions may be responsible for the generation of positive and the negative psychotic symptoms of schizophrenia.     

Fos imaging reveals differential neuronal activation of areas of rat temporal cortex by novel and familiar sounds

To provide information about the possible regions involved in auditory recognition memory, this study employed an imaging technique that has proved valuable in the study of visual recognition memory. The technique was used to image populations of neurons that are differentially activated by novel and familiar auditory stimuli, thereby paralleling previous studies of visual familiarity discrimination. Differences evoked by novel and familiar sounds in the activation of neurons were measured in different parts of the rat auditory pathway by immunohistochemistry for the protein product (Fos) of the immediate early gene c-fos. Significantly higher counts of stained neuronal nuclei (266 +/- 21/mm2) were evoked by novel than by familiar sounds (192 +/- 17/mm2) in the auditory association cortex (area Te3; AudA). No such significant differences were found for the inferior colliculus, primary auditory cortex, postrhinal cortex, perirhinal cortex (PRH), entorhinal cortex, amygdala or hippocampus. These findings are discussed in relation to the results of lesion studies and what is known of areas involved in familiarity discrimination for visual stimuli. Differential activation is produced by novel and familiar individual stimuli in sensory association cortex for both auditory and visual stimuli, whereas the PRH is differentially activated by visual but not auditory stimuli. It is suggested that this latter difference is related to the nature of the particular auditory and visual stimuli used.     

Spontaneous Regional Brain Activity in Healthy Individuals is Nonlinearly Modulated by the Interaction of ZNF804A rs1344706 and COMT rs4680 Polymorphisms

ZNF804A rs1344706 has been identified as one of the risk genes for schizophrenia.However,the neural mechanisms underlying this association are unknown.Given that ZNF804A upregulates the expression of COMT,we hypothesized that ZNF804 A may influence brain activity by interacting with COMT.Here,we genotyped ZNF804A rs1344706 and COMT rs4680 in 218 healthy Chinese participants.Amplitudes of low-frequency fluctuations(ALFFs)were applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680.The ALFFs of the bilateral dorsolateral prefrontal cortex showed a significant ZNF804A rs1344706 x COMT rs4680 interaction,manifesting as a U-shaped modulation,presumably by dopamine signaling.Significant main effects were also found.These findings suggest that ZNF804A affects the resting-state functional activation by interacting with COMT,and may improve our understanding of the neurobiological effects of ZNF804A and its association with schizophrenia.     

中国抗精神病药物治疗精神分裂症患者P300潜伏期和波幅变化的Meta分析(英文)

背景事件相关电位研究表明,精神分裂症患者的认知功能损害与P300的潜伏期和波幅有关,但尚不清楚这些认知功能的改变是否会随着药物治疗而改变。目的汇集中国的随访研究,确定抗精神病药物治疗与P300成分改变的关系。方法手工和电子检索1982年1月至2011年12月在中国进行的、以中文或英文发表的文献,内容为抗精神病药物治疗前后精神分裂症患者P300的潜伏期和波幅变化。2位评定者对12项符合Meta分析纳入标准的研究独立进行分析。12项研究中有17个样本的P300波幅峰值具有同质性,因而采用固定效应模型计算汇集的标准化效应值(pooledstandardized effect size,PSES);但P300潜伏期数值具有异质性,因而采用随机效应模型计算PSES。采用Egger’s和Begg’s检验及倒漏斗图分析发表性偏倚。结果汇集样本的611例受试者中,治疗前后完成P300潜伏期和波幅测试的502例(82.2%)纳入Meta 分析。发现抗精神病药物治疗与P300波幅微小但显著的增加有关(PSES=0.39, 95% CI [0.26, 0.51], z=6.14, p<0.001)及P300潜伏期微小但显著的减少有关(PSES= -0.29, 95% CI [-0.51, -0.07]; z=2.58; p=0.010)。无显著的发表偏移。结论既往西方的Meta分析主要是基于横断面研究,与此不同,中国的这一精神分裂症患者治疗随访研究的Meta分析发现P300波幅和潜伏期均随药物治疗而改变。提示P300成分,特别是P300波幅,可能是精神分裂症患者药物治疗期间监测认知功能变化的有价值的生物学标记。     

青少年精神分裂症和孤独症儿童的听觉P300比较研究

目的 探讨青少年精神分裂症（AS）和孤独症儿童（AC）在P300检测中的不同特点.方法 收集符合ICD-10诊断标准的32例AS患者和30例AC以及40例健康儿童对照组（NC）.使用美国仪器以及＂听觉靶-非靶刺激序列＂为诱发事件,完成P300检测.结果 （1）AS组、AC组和NC组在靶潜伏期Oz脑区N2以及在靶波幅Oz脑区P3和非靶波幅Oz脑区P2上均有显著差异（P＜0.01）;（2）AC主成分N2表现为延迟,与NC组和AS组有极显著性差异（P＜0.01）;（3）AS组和AC组靶波幅P3和非靶波幅P2均见降低,与NC组比较具有显著性差异（P＜0.05～＜0.01）.结论 P300可作为AS和AC辅助评定的一个脑电生理学指标.P300检查可作为儿童精神科的必查项目.     

阿尔茨海默病和血管性痴呆听觉事件相关电位P300比较研究

目的 探讨阿尔茨海默病（AD）和血管性痴呆（VD）在听觉事件相关电位P300检测中的不同特点。方法 收集符合ICD-10诊断标准的30例AD和36例VD患者,并以35例健康老人作对照组（NC）。使用丹麦仪器以及“听觉靶-非靶刺激序列”为诱发事件,完成P300检测。结果 （1）3组在靶潜伏期Cz脑区N2以及在靶波幅Cz脑区P2、P3和非靶波幅Cz脑区P2上均有显著差异（P〈0．01）。（2）AD主成分N2表现为延迟,与NC组和VD组有极显著性差异（P〈0．01）。（3）AD组和VD组靶波幅P3和非靶波幅P2均见降低,与NC组比较也有显著性差异（P〈0．05-〈0．01）。结论 提示作为反映AD和VD认知功能障碍的客观生理指标,P300有可能作为AD和VD辅助诊断的一个脑电生理学标志。P300检查可作为老年神经精神科的必查项目。     

Neurodevelopmental patterns of visual P3b in association with familial risk for alcohol dependence and childhood diagnosis.

BACKGROUND: The P3b component of the event-related potential (ERP) has frequently been reported to be reduced in children and adolescents at high risk for developing alcoholism relative to control children and adolescents without familial loading for alcohol dependence. P300 amplitude changes during development for all children. Previously it has been shown that high-risk offspring display a pattern in which the amplitude is lower at age 8 with a smaller rate of change during adolescence. METHODS: Admixture analysis was applied to data obtained for those children and adolescents having five or more annual assessments of ERPs to determine if multiple P3b growth patterns exist. The P3b amplitude patterns obtained were related to risk status, concurrent presence of childhood psychopathology (internalizing or externalizing), and age of onset to develop a diagnosis. RESULTS: A pattern characterized by lower P3b amplitude at study entry and a slower rate of change during child and adolescent development (pattern 3) was most often associated with high-risk status in boys and high-risk status in combination with the presence of a childhood diagnosis in girls. Pattern 3 was significantly related to the overall presence of childhood psychopathology (internalizing or externalizing) and to the presence of an Axis I diagnosis at young adult follow-up. CONCLUSIONS: The developmental pattern previously described for offspring at high risk for developing alcoholism because of their familial/genetic background was confirmed. Admixture analysis has refined this observation and suggests that among all children and adolescents tested, three developmental patterns can be identified, one of which is most often seen in association with male high-risk children and adolescents.     

A genetic association study of dopamine metabolism-related genes and chronic headache with drug abuse

To assess the role of dopamine metabolism-related genes in the genetic liability to chronic headache with drug abuse (DA). We performed a genetic association study using four functional polymorphisms of the dopamine receptor 4 (DRD4), dopamine transporter (DAT), mono-amino-oxidase A (MAOA) and cathecol-O-methyl-transferase (COMT) genes in 103 patients with chronic daily headache associated with DA (CDHDA). Control samples were 117 individuals without headache or DA (controls) and 101 patients with episodic migraine without aura and without DA (MO). No differences were found at the COMT and MAOA genes among the three groups investigated. Allele 4 of DRD4 was significantly overrepresented in patients with MO compared with both controls and CDHDA. Allele 10 of the DAT gene was significantly underrepresented in patients with CDHDA when compared with the MO group. Genetic variability at the DRD4 gene is involved in the predisposition to episodic MO but not to DA, while liability to CDHDA may involve genetic variability at the DAT gene in comparison with episodic MO.     

A novel test of conditioned inhibition correlates with personality measures of schizotypy and reward sensitivity

Conditioned inhibition is demonstrated when the meaning of one signal (conditioned stimulus, CS) is qualified by another (conditioned inhibitor, CI). Whilst the CS presented alone reliably predicts the outcome (unconditioned stimulus, US), when presented in conjunction with the CI the otherwise expected US will not occur. Conditioned inhibition has long been established in animal research but there have been difficulties in establishing reliable procedures suitable for use in human research. Such procedures are necessary to investigate disorders in which cognitive inhibitory mechanisms are known to be deficient, e.g., schizophrenia. In healthy participants, individual differences in the tendency to show conditioned inhibition should be related to personality measures of cognitive inhibition. In the present study, this was measured using an automated test procedure, in which visual stimuli predict the occurrence or non-occurrence of a visual outcome US, and BIS/BAS and schizotypy scales. Conditioned inhibition was reliable across two alternative test variants, in which the non-occurrence of the US was specified differently, and was confirmed by summation tests. The level of CI shown was positively associated with BAS Reward Responsiveness but did not correlate significantly with any of the other BIS/BAS scales. Conversely, the level of CI shown was negatively associated with schizotypy. We suggest that this novel conditioned inhibition task should now be applied to investigate a range of disorders that have some basis in dysfunctional inhibitory processes, such as schizophrenia.     

Identification of four novel polymorphisms in the Aalpha and gamma fibrinogen genes and analysis of association with plasma levels of the protein

Four novel polymorphisms were identified in the fibrinogen gene cluster. Three of them were localized in the promoter regions of the Aalpha-chain (alpha -128 C/G, alpha -58 G/A) or the gamma-chain (gamma -239 A/G) gene, while the remaining one was identified in intron 9 of the gamma-chain gene (gamma 7792 C/T). Genotype distributions for these polymorphisms were analyzed in 200 healthy Italian individuals and were in Hardy-Weinberg equilibrium. Since high levels of plasma fibrinogen have been associated with an increased risk of cardiovascular disease and genetic variations have been evaluated as thrombotic risk predictors, we analyzed their role in determining the plasma levels of this protein. Owing to the low frequency of the rare allele of alpha -128 C/G and gamma -239 A/G polymorphisms, association with plasma fibrinogen levels was investigated for only alpha -58 G/A and gamma 7792 C/T. We also investigated in the same population two previously identified polymorphisms in the fibrinogen gene cluster (alpha TaqI and beta -455 G/A) chosen for their widely studied association with plasma fibrinogen levels. In the multivariate linear regression analysis, no statistically significant association with plasma fibrinogen levels was found.