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In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.
Mol Psychiatry 2006 Sep
PMID:Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. 1681 33

Anorexia nervosa is a serious eating disorder with the highest mortality rate of any psychiatric disorder. The DSM-IV classification differentiates two AN types: the restricting type (AN-R) and the binge-eating/purging type (AN-BP). Leptin (LEP) levels can be thought of as a signal to the body of its energy reserves. The leptin receptor (including all its mRNA isoforms) is expressed in many tissues. Our aim was to discover the transcript expression profile of the LEP receptor-coding gene in the peripheral blood mononuclears in AN-R and AN-BP patients. Three young women suffering from Anorexia nervosa (one with AN-BP and two with AN-R) took part in the study, along with three non-anorexic subjects as our reference group. LEP receptor gene expression was examined using the oligonucleotide microarray method (HG-U133A, Affymetrix). The results were normalized using RMAExpress. Next, the accumulation analysis method was used (clustering). Hierarchical clustering resulted in three groups of separate clusters. The first group (cluster I) consisted of AN-R patients. The next group (cluster II) consisted of reference group patients suffering from different psychic disorders not related to eating disorders. Cluster III consisted of two patients--the first with AN-BP and the second with an adaptive disorder.
Cell Mol Biol Lett 2006
PMID:The transcript expression profile of the leptin receptor-coding gene assayed with the oligonucleotide microarray technique--could this be an anorexia nervosa marker? 1684 49

Bipolar affective disorder is a severe psychiatric disorder with a strong genetic component but unknown pathophysiology. We used microarray technology to determine the expression of approximately 22,000 mRNA transcripts in post-mortem tissue from two brain regions in patients with bipolar disorder and matched healthy controls. Dorsolateral prefrontal cortex tissue from a cohort of 70 subjects and orbitofrontal cortex tissue from a separate cohort of 30 subjects was investigated. The final analysis included 30 bipolar and 31 control subjects for the dorsolateral prefrontal cortex and 10 bipolar and 11 control subjects for the orbitofrontal cortex. Differences between disease and control groups were identified using a rigorous statistical analysis with correction for confounding variables and multiple testing. In the orbitofrontal cortex, 393 differentially expressed transcripts were identified by microarray analysis and a representative subset was validated by quantitative real-time PCR. Pathway analysis revealed significant upregulation of genes involved in G-protein coupled receptor signalling and response to stimulus (in particular the immune response), while genes relating to the ubiquitin cycle and intracellular transport showed coordinated downregulation in bipolar disorder. Additionally, several genes involved in synaptic function were significantly downregulated in bipolar disorder. No significant changes in gene expression were observed in the dorsolateral prefrontal cortex using microarray analysis or quantitative real-time PCR. Our findings implicate the orbitofrontal cortex as a region prominently involved in bipolar disorder and indicate that diverse processes are affected. Overall, our results suggest that dysregulation of the ubiquitin pathway and synaptic function may be central to the disease process.
Mol Psychiatry 2006 Oct
PMID:Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes. 1689 94

Suicidal behavior, which ranks among the top 10 causes of death worldwide, is an important public-health problem and a psychiatric disorder, which has been the subject of considerable study. Studies have shown association between the serotonin transporter (5-HTT) gene and suicidal behavior, although a proportion of alternative studies have produced contrary results both in terms of positive and negative findings, possibly reflecting inadequate statistical power and the use of different populations. Using the cumulative data from recent years in both European and, more particularly, Asian populations, this updated meta-analysis seeks to examine whether the aggregate data provide evidence of statistical significance, and to clarify the contradictory findings suggested by previous studies. It covers all published studies using multiple research methods up to January 2006. Compared with a previous meta-analysis, which found no association between the 5-HTTLPR polymorphism and suicidal behavior (P=0.38), the current results (39 studies) suggest a significant association with a P-value of 0.0068 (overall odds ratio=0.88 (0.8,0.97)), and supports the involvement of the brain 5-HTT in the pathogenesis of suicidal behavior.
Mol Psychiatry 2007 Jan
PMID:Meta-analysis supports association between serotonin transporter (5-HTT) and suicidal behavior. 1696 68

The prefrontal cortex, a part of the limbic-thalamic-cortical network, participates in regulation of mood, cognition and behavior and has been implicated in the pathophysiology of major depressive disorder (MDD). Many neuropsychological studies demonstrate impairment of working memory in patients with MDD. However, there are few functional neuroimaging studies of MDD patients during working memory processing, and most of the available ones included medicated patients or patients with both MDD and bipolar disorder. We used functional magnetic resonance imaging (fMRI) to measure prefrontal cortex function during working memory processing in untreated depressed patients with MDD. Fifteen untreated individuals with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition recurrent MDD (mean age+/-s.d.=34.3+/-11.5 years) and 15 healthy comparison subjects (37.7+/-12.1 years) matched for age, sex and race were studied using a GE/Elscint 2T MR system. An echo-planar MRI sequence was used to acquire 24 axial slices. The n-back task (0-back, 1-back and 2-back) was used to elicit frontal cortex activation. Data were analyzed with a multiple regression analysis using the FSL-FEAT software. MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls (P<0.01), although task performance was similar in the two groups. Furthermore, the patients showed significant anterior cingulate cortex activation during the task, but the comparison subjects did not (P<0.01). This study provides in vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD.
Mol Psychiatry 2007 Feb
PMID:Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder. 1698 90

Several microbes have been suspected as pathogenetic factors in schizophrenia. We have previously observed increased frequencies of chlamydial infections and of human lymphocyte antigen (HLA)-A10 in independent studies of schizophrenia. Our aim here was to analyze frequencies of three types of Chlamydiaceae in schizophrenic patients (n=72), random controls (n=225) and hospital-patient controls (n=36), together with HLA-A genotypes. Patients were diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders-IV. Blood samples were collected at the beginning of hospitalization and analyzed with Chlamydiaceae species-specific polymerase chain reaction (PCR). Control panels consisted of randomly selected volunteers and hospitalized, non-schizophrenic patients. We found chlamydial infection in 40.3% of the schizophrenic patients compared to 6.7% in the controls. The association of schizophrenia with Chlamydiaceae infections was highly significant (P=1.39 x 10(-10), odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P=2.81 x 10(-7), OR=24.39). Schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P=8.03 x 10(-5), OR=50.00). Chlamydophila infections represent the highest risk factor yet found to be associated with schizophrenia. This risk is even further enhanced in carriers of the HLA-A10 genotype.
Mol Psychiatry 2007 Mar
PMID:Associations between Chlamydophila infections, schizophrenia and risk of HLA-A10. 1710

1. Neuroactive steroids are steroid hormones that exert rapid, nongenomic effects at ligand-gated ion channels. There is increasing awareness of the possible role of these steroids in the pathology and manifestation of symptoms of psychiatric disorders. The aim of this paper is to review the current knowledge of neuroactive steroid functioning in the central nervous system, and to assess the role of neuroactive steroids in the pathophysiology and treatment of symptoms of schizophrenia, depression, and anxiety disorders. Particular emphasis will be placed on GABAA receptor modulation, given the extensive knowledge of the interactions between this receptor complex, neuroactive steroids, and psychiatric illness. 2. A brief description of neuroactive steroid metabolism is followed by a discussion of the interactions of neuroactive steroids with acute and chronic stress and the HPA axis. Preclinical and clinical studies related to psychiatric disorders that have been conducted on neuroactive steroids are also described. 3. Plasma concentrations of some neuroactive steroids are altered in individuals suffering from schizophrenia, depression, or anxiety disorders compared to values in healthy controls. Some drugs used to treat these disorders have been reported to alter plasma and brain concentrations in clinical and preclinical studies, respectively. 4. Further research is warranted into the role of neuroactive steroids in the pathophysiology of psychiatric illnesses and the possible role of these steroids in the successful treatment of these disorders.
Cell Mol Neurobiol 2007 Aug
PMID:The relevance of neuroactive steroids in schizophrenia, depression, and anxiety disorders. 1723 96

Our knowledge about the neurobiology of suicide is limited. It has been proposed that suicidal behavior generally requires biological abnormalities concomitant with the personality trait of impulsivity/aggression, besides an acute psychiatric illness or psychosocial stressor. We investigated fronto-limbic anatomical brain abnormalities in suicidal and non-suicidal adult female patients with unipolar depression. Our sample consisted of seven suicidal unipolar patients, 10 non-suicidal unipolar patients and 17 healthy female comparison subjects. The criterion for suicidality was one or more documented lifetime suicide attempts. A 1.5T GE Signa Imaging System running version Signa 5.4.3 software was used to acquire the magnetic resonance imaging images. All anatomical structures were measured blindly, with the subjects' identities and group assignments masked. We used analysis of covariance with age and intracranial volume as covariates and the Tukey-Kramer procedure to compare suicidal patients, non-suicidal patients and healthy comparison subjects. Suicidal patients had smaller right and left orbitofrontal cortex gray matter volumes compared with healthy comparison subjects. Suicidal patients had larger right amygdala volumes than non-suicidal patients. Abnormalities in the orbitofrontal cortex and amygdala in suicidal patients may impair decision-making and predispose these patients to act more impulsively and to attempt suicide.
Mol Psychiatry 2007 Apr
PMID:Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder. 1738 3

Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder encompassing a spectrum of symptoms involving deficits to a range of cognitive, psychomotor and emotional processes. As is the norm for aetiological studies into the majority of psychiatric phenotypes, particular focus has fallen on the interplay between genetic and environmental factors. There are, however, several epidemiological, clinical and molecular peculiarities associated with MDD that are hard to explain using traditional gene- and environment-based approaches. Our goal in this study is to demonstrate the benefits of looking beyond conventional 'DNA+environment' and 'DNA x environment' aetiological paradigms. Epigenetic factors - inherited and acquired modifications of DNA and histones that regulate various genomic functions occurring without a change in nuclear DNA sequence - offer new insights about many of the non-Mendelian features of major depression, and provide a direct mechanistic route via which the environment can interact with the genome. The study of epigenetics, especially in complex diseases, is a relatively new field of research, and optimal laboratory techniques and analysis methods are still being developed. Incorporating epigenetic research into aetiological studies of MDD thus presents a number of methodological and interpretive challenges that need to be addressed. Despite these difficulties, the study of DNA methylation and histone modifications has the potential to transform our understanding about the molecular aetiology of complex diseases.
Mol Psychiatry 2007 Sep
PMID:Molecular studies of major depressive disorder: the epigenetic perspective. 1742 Jul 65

Family studies have demonstrated genetic influences on environmental exposure: the phenomenon of gene-environment correlation (rGE). A few molecular genetic studies have confirmed the results, but the identification of rGE in studies that measure genes and environments faces several challenges. Using examples from studies in psychology and psychiatry, we integrate the behavioral and molecular genetic literatures on rGE, describe challenges in identifying rGE and discuss the implications of molecular genetic findings of rGE for future research on gene-environment interplay and for attempts to prevent disease by reducing environmental risk exposure. Genes affect environments indirectly, via behavior and personality characteristics. Associations between individual genetic variants and behaviors are typically small in magnitude, and downstream effects on environmental risk are further attenuated by behavioral mediation. Genotype-environment associations are most likely to be detected when the environment is behaviorally modifiable and highly specified and a plausible mechanism links gene and behavior. rGEs play an important causal role in psychiatric illness. Although research efforts should concentrate on elucidating the genetic underpinnings of behavior rather than the environment itself, the identification of rGE may suggest targets for environmental intervention even in highly heritable disease. Prevention efforts must address the possibility of confounding between rGE and gene-environment interaction (G x E).
Mol Psychiatry 2007 May
PMID:Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. 1745 60


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