精神分裂症患者外周血白细胞基因差异表达的基因芯片研究

目的 研究健康人及精神分裂症患者外周血白细胞基因表达谱，分析精神分裂症患者基因表达水平的变化。方法 取6例精神分裂症患者和6名健康人的外周血白细胞，提取总。RNA，在反转录cDNA时，分别用Cy3、cy5两种激发波长荧光标记，获得两组样本cDNA探针。将两组探针混合后与含8464条人类基因表达谱芯片杂交，扫描、分析杂交结果。结果 当Cy5与Cy3比值大于2或小于0．5时，在6对样本7次试验中有13条基因在精神分裂症患者中均下调表达。当Cy5与Cy3比值大于1．5或小于0．7时，在6对样本7次试验共同出现差异的基因有31条，其中2条基因在精神分裂症患者中上调表达，29条下调表达。结论 精神分裂症患者的一些基因表达水平与正常人存在差异，这些基因主要与免疫、神经细胞发育、神经传递、髓鞘形成有关。     

一个精神分裂症多发家系染色体候选区域的连锁分析

目的 探讨1q21-22，1q32-44，5q21—33，6p24—22，8p22—21，10p15—11，11q23—24，11p15，12q23—24，13q32—34，22q11—12，9q34，16p13，12q13，17q25及19q13等染色体候选区域与精神分裂症的连锁关系。方法 选择候选染色体区域的微卫星标志，对湖南省永州市一个汉族精神分裂症多发家系进行基因组扫描。用Linkage5．1软件包及Genehunter2．1软件包进行参数和非参数连锁分析，并构建最可能的单体型。结果在染色体11q23．2-24．2区域获得3个连续高的多点非参数分析LOD值，在D11s925处获得的峰值为4．33（P=0．016），超过显著性连锁的阈值。与D11s925相邻的D11s898及D11s4151在多点非参数分析中的LOD值分别为1．57和3．82。对11号染色体上的6个微卫星标志进行单体型分析，D11s902与D11s898之间存在重组，提示可能的疾病基因在D11s902远端。结论 11q22．1-24．2区域可能包含有精神分裂症的易感基因。     

Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary study

Microarray studies can be used to examine expression levels for large numbers of genes simultaneously and may be applied to identify genes involved in schizophrenia. A microarray with 1127 brain-relevant genes was used to screen relative gene expression in the dorsolateral prefrontal cortex (DLPFC) from three pools of patients with schizophrenia (n = 15) and three matched control pools (n = 15). Pooling of tissue samples was employed as a strategy to detect changes in gene expression that are consistently found across individual cases of schizophrenia. Differences in gene expression were examined by z-ratios in addition to traditional normalized ratios. Three genes that showed consistently decreased expression in schizophrenia by both z-ratio differences and decreased normalized numerical ratios were identified. These were histidine triad nucleotide-binding protein (HINT), ubiquitin conjugating enzyme E2N (UBE2N) and glutamate receptor, ionotropic, AMPA 2 (GRIA2). Moreover, HINT gene expression was decreased to a similar degree in a prior study. In addition, a decrease in AMPA receptor expression is consistent with a decrease in glutamate synaptic function. These results are subject to limitations based on variations inherent to human subjects and tissue samples, possible effects of neuroleptic treatment, and the requirement for verification using independent techniques.     

Application of cDNA microarrays to examine gene expression differences in schizophrenia

Using cDNA microarrays we have investigated gene expression patterns in brain regions of patients with schizophrenia. A cDNA neuroarray, comprised of genes related to brain function, was used to screen pools of samples from the cerebellum and prefrontal cortex from a matched set of subjects, and middle temporal gyrus, from a separate subject cohort. Samples of cerebellum and prefrontal cortex from neuroleptic naive patients were also included. Genes that passed a 3% reproducibility criterion for differential expression in independent experiments included 21 genes for drug-treated patients and 5 genes for drug-naive patients. Of these 26 genes, 10 genes were increased and 16 were decreased. Many of the differentially expressed genes were related to synaptic signaling and proteolytic functions. A smaller number of these genes were also differentially expressed in the middle temporal gyrus. The five genes that were differentially expressed in two brain regions from separate cohorts are: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide; sialyltransferase; proteasome subunit, alpha type 1; ubiquitin carboxyl-terminal esterase L1; and solute carrier family 10, member 1. Identification of patterns of changes in gene expression may lead to a better understanding of the pathophysiology of schizophrenia disorders.     

Gender differences in the clinical expression of schizophrenia.

Gender differences have been reported for a variety of clinical measures in patients with schizophrenia. Clinical characterization may be helpful in identifying symptom clusters which can then be linked to underlying brain function. In this study 74 men and 33 women meeting DSM-IIIR criteria for schizophrenia were studied off medication and rated on measures of symptom type and severity, as well as premorbid and current function. Men were more severely impaired in ratings of negative symptoms, while positive symptoms were not significantly different. There were also differences in premorbid and current functioning, with women manifesting better social functioning than men.     

Clinical polydiagnostic studies in a large Swedish pedigree with schizophrenia

Summary A polydiagnostic computerized diagnostic system for psychosis was used in a Swedish family complex, and 51 patients with psychiatric symptomatology were examined with eight main diagnostic systems for schizophrenia and three systems for schizophrenic subgroups. All patients fulfilled the criteria for schizophrenia according to Taylor et al., 50 according to Carpenter, 41 according to RDC, and 31 of the 51 according to DSM-III and DSM-III-R. The hypothesis that the patients in the Swedish family complex differ from other phenotypes of schizophrenia must be refuted based on the data of the present study.     

A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree

Schizophrenia is a common and etiologically heterogeneous disorder. Although inheritance of schizophrenic syndromes is complex with genetic and environmental factors contributing to the clinical phenotype, periodic catatonia, a familial subtype of catatonic schizophrenia, appears to be transmitted in an autosomal dominant manner. We report here that a Leu309Met mutation in WKL1, a positional candidate gene on chromosome 22q13.33 encoding a putative non-selective cation channel expressed exclusively in brain, co-segregates with periodic catatonia in an extended pedigree. Structural analyses revealed that this missense mutation results in conformational changes of the mutant protein. Our results not only underscore the importance of genetic mechanisms in the etiology of schizophrenic syndromes, but also provide a better understanding of the pathogenesis and incapacitating course of catatonic schizophrenia and related disorders.     

Neurocognitive endophenotypes in a multiplex multigenerational family study of schizophrenia

OBJECTIVE: Genetic factors contribute to the development of schizophrenia where cognitive dysfunction is a hallmark. The purpose of this article was to examine computerized neurocognitive measures as candidate endophenotypic markers of liability for schizophrenia in a genetically informative cohort. METHOD: European Americans from 35 multiplex multigenerational families (N=349) and healthy participants (N=154) underwent clinical assessments and neurocognitive measurements and provided blood samples. The neurocognitive measures included performance (accuracy and speed) from a computerized battery that assessed abstraction/mental flexibility; attention; verbal, face, and spatial memory; spatial processing; sensorimotor processing; and emotion intensity discrimination. RESULTS: Probands, relatives, and comparison subjects differed from each other in performance. Probands demonstrated greatest impairment relative to comparison subjects, followed by family members. Liability for schizophrenia affected the speed-accuracy tradeoff differently for specific neurocognitive domains. Significant heritability estimates were obtained for accuracy of verbal, facial, and spatial memory and spatial and emotion processing. For speed, estimates of heritability were significant for abstraction/mental flexibility, attention, face memory, and spatial and sensorimotor processing. CONCLUSIONS: In a multigenerational multiplex design, the authors demonstrated that neurocognitive measures are associated with schizophrenia, differentiate unaffected relatives from comparison subjects, and may have significant presumed heritability. Therefore, they are endophenotypes suitable for genetic studies. Accuracy and speed can be differentially sensitive to presumed genetic liability.     

Gene polymorphism and gene expression in schizophrenia

The author reviews relevant data on the neuropathology and molecular genetics of schizophrenia. Anatomical alterations are localized mainly in the hippocampus, dorsal thalamus and dorsolateral prefrontal cortex, and involve the morphology and molecular structure of the neurons and synapses. Several susceptibility genes [including COMT, dysbindin, neuregulin, DISCI, RGS4, GRM3, G72, PPP3CC, CHRNA7, PRODH2, Aktl, 5qGABA(A)] having physiological function in the brain have been identified and this supports the view of schizophrenia as a disorder of cerebral synaptic function. NMDA receptor-mediated glutamate transmission may be particularly involved, but disturbances of dopamine and GABA signalling seem to be linked as well. Based on recent data, an agreement is emerging between the roles of the genes on the molecular and synaptic levels and the understanding of the disorder at the neural systems level.     

Human blood analysis reveals differences in gene expression of catecholamine-regulated protein 40 (CRP40) in schizophrenia

Heat shock proteins (HSPs) are important players in neurodegeneration and psychiatric disorders. We previously reported significant reductions of a 40-kDa Catecholamine Regulated Protein (CRP40) in schizophrenia post-mortem brain specimens. This study investigated whether gene expression of CRP40 is altered in living subjects with schizophrenia. CRP40 mRNA was analyzed in white blood cells of first episode and chronic/treated schizophrenia subjects compared to healthy controls. Significant reductions in CRP40 mRNA were found among first episode schizophrenia subjects and chronic schizophrenia subjects compared to healthy controls (p < 0.05 for both). These results suggest a possible functional role of CRP40 in the pathogenesis of schizophrenia.     

Three-cohort targeted gene screening reveals a non-synonymous TRKA polymorphism associated with schizophrenia

Schizophrenia is a complex neurodevelopmental disorder that is thought to be induced by an interaction between predisposing genes and environmental stressors. To identify predisposing genetic factors, we performed a targeted (mostly neurodevelopmental) gene approach involving the screening of 396 selected non-synonymous single-nucleotide polymorphisms (SNPs) in three independent Caucasian schizophrenia case-control cohorts (USA, Denmark and Norway). A meta-analysis revealed ten non-synonymous SNPs that were nominally associated with schizophrenia, nine of which have not been previously linked to the disorder. Risk alleles are in TRKA (rs6336), BARD1 (rs28997576), LAMA5 (rs3810548), DKK2 (rs7037102), NOD2 (rs2066844) and RELN (rs2229860), whereas protective alleles are in NOD2 (rs2066845), NRG1 (rs10503929), ADAM7 (rs13259668) and TNR (rs859427). Following correction for multiple testing, the most attractive candidate for further study concerns SNP rs6336 (q = 0.12) that causes the substitution of an evolutionarily highly conserved amino acid residue in the kinase domain of the neurodevelopmentally important receptor TRKA. Thus, TRKA signaling may represent a novel susceptibility pathway for schizophrenia.     

Sex differences in schizophrenia

Evidence suggests sex differences in schizophrenia reflect differences in both neurodevelopmental processes and social effects on disease risk and course. Male:female incidence approximates 1.4:1 but at older onset women predominate. Prevalence differences appear smaller. Men have poorer premorbid adjustment and present with worse negative and less depressive symptoms than women, which may explain their worse medium term outcome according to a range of measures. Substance abuse is a predominantly male activity in this group, as elsewhere. Findings of sex differences in brain morphology are inconsistent but occur in areas that normally show sexual dimorphism, implying that the same factors are important drivers of sex differences in both normal neurodevelopmental processes and those associated with schizophrenia. There are sex differences in antipsychotic responses but sex-specific endocrine effects on illness and response to antipsychotics are potentially complex. Oestrogen's role as an adjunctive medication is not yet clear due to methodological differences between the few randomized controlled trials. Services that are sensitive to differences in gender can better meet their patients’ specific needs and potentially improve outcome.     

Sex differences in schizophrenia

Evidence suggests sex differences in schizophrenia reflect differences in both neurodevelopmental processes and social effects on disease risk and course. Male:female incidence approximates 1.4:1 but at older onset women predominate. Prevalence differences appear smaller. Men have poorer premorbid adjustment and present with worse negative and less depressive symptoms than women, which may explain their worse medium term outcome according to a range of measures. Substance abuse is a predominantly male activity in this group, as elsewhere. Findings of sex differences in brain morphology are inconsistent but occur in areas that normally show sexual dimorphism, implying that the same factors are important drivers of sex differences in both normal neurodevelopmental processes and those associated with schizophrenia. There are sex differences in antipsychotic responses but sex-specific endocrine effects on illness and response to antipsychotics are potentially complex. Oestrogen's role as an adjunctive medication is not yet clear due to methodological differences between the few randomized controlled trials. Services that are sensitive to differences in gender can better meet their patients' specific needs and potentially improve outcome.     

精神分裂症的性别差异

目的:探讨精神分裂症患者的性别差异。方法:收集240例不同性别精神分裂症患者的首次发病年龄、病程、阳性家族史、临床症状、病前人格和诊断分型等资料,并进行分析比较。结果:首次发病年龄、病程和阳性家族史无性别差异,读心症、钟情妄想、其他妄想、思维逻辑性障碍和怪异行为等阳性症状在男性患者组和女性患者组中的分布差异有显著性,其他阳性症状及阴性症状在两组中的分布差异无显著性。结论:精神分裂症患者的阳性症状存在性别差异,女性精神分裂症患者的临床症状多表现为阳性症状。     

Sex differences in schizophrenia

Demographic and clinical characteristics of 275 schizophrenics consecutively admitted to seven hospitals were examined. Males were younger than females when first hospitalized, diagnosed and treated. Psychiatrists rated on two rating scales by using a structured interview to compare the symptomatology. Female schizophrenics were more agitated, inappropriate, silly, irrelevant, over-talkative, and exhibiting more flight of ideas, while male schizophrenics were more slowed, hypoactive, grandiose, withdrawn, and showing more blocking, auditory hallucinations and poor communications. Katz Adjustment Scales were rated by the patients and their relatives. Female schizophrenics were perceived by relatives to be more helpless and withdrawn-depressed than male schizophrenics.     

Gender differences in schizophrenia

Lewine (Psychol. Bull., 90: 432-444, 1981) has proposed sex differences, specific to schizophrenics, in age at first psychiatric hospitalization, age at first reported symptoms, and premorbid social competence. To evaluate Lewine's hypothesis we collected data on 64 schizophrenic and 30 nonschizophrenic psychiatric outpatients. As no interaction between sex and diagnostic groups was found, our data failed to demonstrate sex differences specific and unique to schizophrenia. It is possible that Lewine's evidence is due to a cultural artifact.     

Gender differences in schizophrenia

Sex differences in schizophrenia can be caused by the disease process itself, by genetic and hormonal differences, by differences in the maturation and morphology of the brain and in age- and gender-specific behavioural patterns. These hypotheses will be tested on the major results reported in the literature as well as on different levels (epidemiology, risk factors, animal experiments, a controlled clinical study) on data from the ABC Schizophrenia Study. Symptomatology, lifetime risk and symptom-related course of illness-the latter without consideration of age-show no gender differences. However, until menopause illness onset is delayed and severity of illness is reduced by oestrogen on the level of gene expression and transmitter functioning. Oestrogen has an antagonistic effect on the-familial or exogenous-predisposition to illness. As a result, the age distribution of onset and the severity of first-episode illness in young men and post-menopausal women differ from the normal. First intervention trials with oestrogen substitution of neuroleptic therapy have demonstrated antipsychotic effects. The poorer social course of schizophrenia in men than in premenopausal women is accounted for by men's lower level of social development at illness onset and the subsequent impediment of their further development. Men's socially adverse illness behaviour, too, is a contributing factor. Scarcity of the knowledge of differences in the development, morphology and functioning of the male and female brain does not yet allow any definitive conclusions about gender differences in schizophrenia.     

Gender differences in schizophrenia

men with schizophrenia have an earlier age of onset, a somewhat inferior response to treatment and a generally poorer prognosis than women. These findings can perhaps be explained by the existence of two distinct forms of the illness, one with early onset, primarily affecting men, and one with later onset, primarily affecting women. There is not much evidence for this first view. Alternatively, non-specific cumulative stress factors may impinge selectively on the male, reaching the threshold of demonstrable illness at an earlier age. A third possibility is the existence of specific biological protective factors in the female, such as relatively bilateral representation of left hemisphere functions or relative dopaminergic inhibition by estrogens.