Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have suggested that the alpha 7-nicotinic receptor gene (CHRNA7) may play a role in the pathogenesis of schizophrenia. The alpha 7-nicotinic receptor gene (CHRNA7) is involved in P50 auditory sensory gating deficits, and the genomic locus for this gene lies in the chromosome 15q13-14 regions. The human gene is partially duplicated (exons 5-10) with four novel upstream exons. The marker D15S1360 has been shown to be significantly linked with the phenotype of abnormal P50 suppression in schizophrenia families. The marker L76630 is 3 kb in the 3' direction from the last exon of the CHRNA7 gene and is located in the duplicated region. The function of the two L76630 copies is unknown. We genotyped three polymorphic markers D15S1360, D15S165, and L76630 that are localized in a genomic fragment containing the CHRNA7 in 31 Azorean schizophrenia families/trios (including 41 schizophrenia individuals and 97 unaffected families members). An overall analysis utilizing the family-based association test revealed significant linkage disequilibrium between L76630 and schizophrenia (P = 0.0004). Using the extended transmission disequilibrium test and limiting the analysis to one triad per family, transmission disequilibrium of D15S1360 was near significance (P = 0.078). The 15q13 region overlaps with the location of two well-known genomically imprinted disorders: Angelman syndrome and Prader-Willi syndrome. Therefore, we investigated maternal and paternal meioses. We found significant transmission disequilibrium for D15S1360 through paternal transmission (P = 0.0006) in our schizophrenia families. The L76630 marker showed a significant disequilibrium in maternal transmissions (P = 0.028). No parent-of-origin effect was found in D15S165. Overall, our results suggest that the CHRNA7 may play a role in schizophrenia in these families. A parent of origin effect may be present and requires further study.
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PMID:Evidence for linkage disequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families. 1180 10

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder of childhood that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD. First, nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers, and nonsmokers. Second, ADHD is a significant risk factor for early initiation of cigarette smoking in children and maternal cigarette smoking appears to be a risk factor for ADHD. Finally, animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity. The nicotinic system has previously been studied in schizophrenia where the neuronal nicotinic acetylcholine receptor alpha 7 subunit gene (CHRNA7) has been implicated in decreased P50 inhibition and attentional disturbances in patients with schizophrenia and in many of their nonschizophrenic relatives. Three known microsatellite markers (D15S165, D15S1043, and D15S1360) near the nicotinic acetylcholine alpha 7 receptor gene, CHRNA7, were studied in 206 ADHD parent-proband trios of children aged 5-16 with ADHD according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ < 70) were excluded from the study. Markers D15S165 and D15S1360 were in linkage disequilibrium. The extended Transmission Disequilibrium Test analyses demonstrated no evidence that variation at the microsatellite markers D15S1360, D15S1043, and D15S165 influences susceptibility to ADHD. However, it remains possible that the CHRNA7 gene and other nicotinic system genes may be involved in conferring susceptibility to ADHD.
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PMID:No association between CHRNA7 microsatellite markers and attention-deficit hyperactivity disorder. 1180 15

We have mapped a sample of 68 families consisting of one or more affected sibling pairs with schizophrenia or schizoaffective disorder with 20 markers spanning all of chromosome 15 to investigate whether there is a locus on chromosome 15 that confers an increased susceptibility to schizophrenia using parametric and nonparametric linkage analyses. Allele sharing identical by descent and multipoint maximum likelihood score (MLS) statistics were employed. Results show excess allele sharing for multiple markers in 15q11.2-q25, a chromosomal region previously found linked to a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, a decrease associated with schizophrenia. Excess allele sharing was found for markers spanning about 48 cM in 15q11.2-q25 (D15S1002-D15S1023). The greatest single point allele sharing was found at D15S659 (62.6%). The multipoint MLS scores were greater than 1.0 in the 30-52 cM interval delimited by ACTC and D15S150, with a maximum value of 2.0 with GENEHUNTER PLUS near D15S1039.
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PMID:Linkage analysis of schizophrenia to chromosome 15. 1180 32

A personal review is presented of the functional basis of activation, withdrawal and unreality, individual differences in schizophrenia that Venables et al. pioneered. Activated and withdrawn syndromes were delineated from the totality of symptoms by classifying unmedicated patients on the basis of lateral asymmetries in electrodermal responses. A neuropsychological syndrome translation led to a syndrome hemispheric imbalance model supported by a literature review disclosing widespread cortical and infracortical involvement extending to motoneurone excitability, with validation from tests of learning, memory and evoked responses including the P300. It is contended that the centrality of arousal, the extensive substrate and the evidence of asymmetry modification with recovery and treatment all implicate specific and nonspecific thalamo-cortical systems whose uncoupling may lead to dysfunction of input, cognition and to unreality symptoms (found inconsistently related to asymmetry). The three syndromes have developmental associations including immune competence, ventricular changes and lateral asymmetry, putative regressive neuronal changes in connectivity and electrocortical measures of connectivity, as well as sensory gating and anomalies of P50 suppression and habituation. Replication of the syndromal structure in psychometric schizotypy indicates that syndrome expression is based on the premorbid personality, compatible with evidence of early determinants of the approach/withdrawal balance in social encounters. Functional considerations for the nature of schizophrenia support neurophysiological approaches to treatment such as neurofeedback.
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PMID:A Janusian perspective on the nature, development and structure of schizophrenia and schizotypy. 1185 83

Auditory P50 and N100 responses reflect preattentive processing, whereas subsequent mismatch negativity (MMN) response indexes memory-based comparison process. Divergent ERP responses have been found in schizophrenia and in Parkinson's disease (PD), which have abnormalities in cerebral dopamine activity. We used simultaneously magnetoencephalography and electroencephalography to investigate, whether a single dose of haloperidol, a dopamine D2-receptor antagonist, modulates preattentive auditory processing using a randomized, double-blind, placebo-controlled crossover design. Our results showed that haloperidol did not alter MMN to frequency and duration changes, whereas the magnetic MMN to frequency change was significantly accelerated. The amplitude and latency changes of the electric and magnetic P50 and N100 were insignificant. Our results indicate that memory-based sound comparison and preceding cortical processing underlying stimulus detection are not attenuated by haloperidol, whereas haloperidol appears to accelerate preattentive sound comparison.
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PMID:Memory-based comparison process not attenuated by haloperidol: a combined MEG and EEG study. 1192 84

In the p50 suppression paradigm, when two auditory stimuli are presented 500 ms apart, the amplitude of the second response (S2), compared with the first (S1), is markedly attenuated in healthy subjects. This is an index of sensory gating. Most schizophrenic patients fail to inhibit the p50 response to the second stimulus, which is assumed to reflect an inhibitory deficit. Adenosine is a neuromodulator with mostly inhibitory activity which is released by physiological stimuli. Since this inhibitory pattern resembles the phenomenon of sensory gating, the contribution of adenosine to p50 suppression was investigated in normal volunteers after treatment with the adenosine antagonist theophylline or placebo. P50 recordings were conducted in thirteen healthy subjects at baseline and 5, 30, 60, and 90 min after oral administration of theophylline (0.66 mg/kg, maximum dose of 500 mg) or placebo in a cross-over design. Baseline results from 17 drug-treated schizophrenic patients were included for comparison. Compared with placebo, theophylline treatment significantly increased P50 ratio (S2/S1) from 0.28 +/- 0.03 to 0.82 +/- 0.11 at 30 min and 0.61 +/- 0.07 at 60 min (mean +/- SEM), which were not significantly different from the schizophrenia group (0.74 +/- 0.05). The increased p50 ratio by theophylline was due to a combined decrease in S1 and increase in S2 amplitude. The impairment of p50 suppression by theophylline in normal subjects suggests a modulatory role of adenosine in sensory gating, which may be related to p50 suppression deficit in schizophrenia and is in agreement with a hypoadenosinergic model of schizophrenia.
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PMID:The adenosine antagonist theophylline impairs p50 auditory sensory gating in normal subjects. 1237 99

Abnormality in the P50 auditory-evoked potential gating is an endophenotype associated with schizophrenia. Biochemical and genetic studies have suggested that the alpha 7 nicotinic acetylcholine receptor (nAChR) is involved in this sensory gating deficit. Two related alpha 7 genes (CHRNA7 and CHRNA7-like gene) resulting from a partial duplication (from exon 5 to exon 10) are present in the human genome. Two types of genetic variation, a large deletion and a -2 base-pair deletion in exon 6 resulting in a truncation of the open reading frame, affect specifically the CHRNA7-like gene. We developed a simple multiplex PCR assay on genomic DNA, allowing the quantification of the number of exons 6 and the distinction of all possible exon 6 genotypes. Genotyping of 70 schizophrenic patients and 77 controls showed that carrying at least one -2 bp deletion of exon 6 did not constitute a risk factor for schizophrenia. In contrast, the distribution of genotypes differed significantly between subjects with normal and abnormal P50 ratios, with an over-representation of genotypes carrying at least one -2 bp deletion of exon 6 among subjects exhibiting an abnormal P50 ratio. We thus conclude that the -2 bp deletion within the CHRNA7-like gene is a risk factor for P50 sensory gating deficit. Interestingly, most of the effect came from the non schizophrenic group, which may suggest that in schizophrenic patients other risk factors account for the large proportion of subjects exhibiting an abnormal P50 ratio.
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PMID:The -2 bp deletion in exon 6 of the 'alpha 7-like' nicotinic receptor subunit gene is a risk factor for the P50 sensory gating deficit. 1239 55

A pilot study was conducted to examine if donepezil could enhance cognitive function in patients with schizophrenia. Fifteen subjects who were on stable olanzapine treatment were entered into a 6-week open-labeled trial of donepezil. Subjects received baseline and end-of-study P50 and neuropsychological assessments. Donepezil treatment resulted in significant improvement in manual dexterity. There were moderate improvements in verbal recall memory and visual memory and processing speed, with smaller changes in P50 and verbal recognition memory. There was no effect on an attention measure. There were no changes in either positive or negative symptoms. These results suggest that cholinergic tone modulation may enhance selective behavioral functions in patients with schizophrenia, but further study is required to delineate the full extent of the potential benefit of this approach.
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PMID:An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia. 1241 39

A continuum of symptoms between "normality" and overt psychosis has been documented in relatives of schizophrenia patients, SPD, and individuals who may be in the early stages of a psychotic illness with "subsyndromal" symptoms. The empirically derived criteria for SPD have been refined to define a clinical phenotype that is linked to schizophrenia. The clinical SPD symptoms define a heterogeneous group of individuals who are often comorbid for Axis I and II disorders, may or may not have a family history of schizophrenia, and are at risk for developing schizophrenia themselves. SPD subjects have similar abnormalities to those observed in schizophrenia patients on various psychophysiologic paradigms designed to study central inhibition, including P50 event-related potential suppression, PPI of the startle response, and the antisaccade task. Because SPD subjects do not have many of the confounding variables observed in schizophrenia patients (i.e., medication effects), these paradigms might represent vulnerability markers that are possible endophenotypes for schizophrenia spectrum illness. Questions still remain as to whether SPD is genotypically linked to schizophrenia but has genes of lesser penetrance, fewer affected genes, lack of a second hit, or perhaps protective factors. It is also possible that SPD, like schizophrenia, is a common final pathway that can come about because of several etiologic factors that affect crucial neurodevelopmental periods. Future directions in SPD work might include the use of vulnerability markers to essentially subtype schizophrenia spectrum patients and create simpler endophenotypes to understand the phenomenologic and neurobiologic substrate. The use of vulnerability markers along with clinical symptoms may help to improve the predictive power for identifying individuals at risk for schizophrenia for early intervention. Finally, genetic studies have yet to be performed in SPD.
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PMID:Vulnerability markers in the schizophrenia spectrum: implications for phenomenology, genetics, and the identification of the schizophrenia prodrome. 1246 63

Neuronal nicotinic acetylcholine receptor expression was examined in schizophrenia. The incidence of smoking in schizophrenia is remarkably high and nicotine has been found to normalize an auditory evoked potential deficit seen in most subjects who suffer from this disease. Antagonists and agonists of a specific subset of this receptor family, the alpha7 nicotinic receptor, were found to regulate the gating of filtering of auditory information in both humans and in an animal model. The alpha7 gene has been cloned and a polymorphic dinucleotide repeat near the gene was used for linkage analysis, showing the alpha7 locus to be linked to the P50 deficit. Expression of the alpha7 receptor, which binds nicotine with low affinity, is reduced in the hippocampus of schizophrenics. [3H]-nicotine binding, a measure of the high affinity nicotinic receptors, was also decreased in schizophrenics and does not increase in response to tobacco use, as is seen in control subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.
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PMID:Nicotinic receptors, smoking and schizophrenia. 1267 15


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