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Elena Jazin

Publications and source records attributed to Elena Jazin.

14 recordsLinked to original sources
PubMed2006

Human QKI, a new candidate gene for schizophrenia involved in myelination.

We have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 Mb region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 Mb haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia.

Adult↗
PubMed2005

Statistical modeling in case-control real-time RT-PCR assays, for identification of differentially expressed genes in schizophrenia.

Aspects of experimental design, statistical modeling, and statistical inference in case-control real-time reverse transcription-polymerase chain reaction (RT-PCR) assays are discussed. The background is mRNA expression data from an investigation of genes previously suggested to be schizophrenia related. Real-time RT-PCR allows large samples of individuals. However, with more individuals than positions per plate, incomplete designs are required. A basic multivariate (for several genes jointly) random-effects analysis of covariance model, incorporating heterogeneity both between and within individuals, is formulated. The use of reference genes to form additional regressors is found to be highly efficient. Because regressions between and within individuals are usually different, it is important first to average over the intraindividual replicates. This has consequences for the influence of plate effects. Topics also discussed are testing for a significant mean disease effect, differential coregulation, and the difficulty of identifying genes affected in only a subgroup of cases.

Analysis of Variance↗
PubMed2005

Serotonin receptor 2C (HTR2C) and schizophrenia: examination of possible medication and genetic influences on expression levels.

The serotonin receptor 2C (HTR2C) gene is of interest in schizophrenia due to its involvement in regulation of dopamine activity in the prefrontal cortex. We have previously reported a decreased expression of HTR2C mRNA levels in the prefrontal cortex of schizophrenia patients. The variability in mRNA expression levels is evaluated here more closely in relation to promoter haplotypes and neuroleptic treatment received by the patients. The decrease in HTR2C mRNA was present in neuroleptic treated individuals and in patients untreated at death, indicating that the lower expression is not a short-term medication effect. Three promoter polymorphisms were used to construct haplotypes. No SNP displayed genotypic or haplotypic association with the disease. Gene expression of HTR2C was not affected by haplotype and the expression decrease in schizophrenia patients was similar in all haplotype combinations (diplotypes). We conclude that the decrease in HTR2C expression in schizophrenia may be related to the disease mechanism rather than to drug treatment. The disease related changes in HTR2C expression are not related to the promoter variants typed in our sample, but could be due to other regulatory variants or trans-acting factors.

Antipsychotic Agents↗
PubMed2005

Genome-wide prediction of human VNTRs.

Polymorphic minisatellites, also known as variable number of tandem repeats (VNTRs), are tandem repeat regions that show variation in the number of repeat units among chromosomes in a population. Currently, there are no general methods for predicting which minisatellites have a high probability of being polymorphic, given their sequence characteristics. An earlier approach has focused on potentially highly polymorphic and hypervariable minisatellites, which make up only a small fraction of all minisatellites in the human genome. We have developed a model, based on available minisatellite and VNTR sequence data, that predicts the probability that a minisatellite (unit size > or = 6 bp) identified by the computer program Tandem Repeats Finder is polymorphic (VNTR). According to the model, minisatellites with high copy number and high degree of sequence similarity are most likely to be VNTRs. This approach was used to scan the draft sequence of the human genome for VNTRs. A total of 157,549 minisatellite repeats were found, of which 29,224 are predicted to be VNTRs. Contrary to previous results, VNTRs appear to be widespread and abundant throughout the human genome, with an estimated density of 9.1 VNTRs/Mb.

Genome, Human↗
PubMed2004

From wild wolf to domestic dog: gene expression changes in the brain.

Despite the relatively recent divergence time between domestic dogs (Canis familiaris) and gray wolves (Canis lupus), the two species show remarkable behavioral differences. Since dogs and wolves are nearly identical at the level of DNA sequence, we hypothesize that the two species may differ in patterns of gene expression. We compare gene expression patterns in dogs, wolves and a close relative, the coyote (Canis latrans), in three parts of the brain: hypothalamus, amygdala and frontal cortex, with microarray technology. Additionally, we identify genes with region-specific expression patterns in all three species. Among the wild canids, the hypothalamus has a highly conserved expression profile. This contrasts with a marked divergence in domestic dogs. Real-time PCR experiments confirm the altered expression of two neuropeptides, CALCB and NPY. Our results suggest that strong selection on dogs for behavior during domestication may have resulted in modifications of mRNA expression patterns in a few hypothalamic genes with multiple functions. This study indicates that rapid changes in brain gene expression may not be exclusive to the development of human brains. Instead, they may provide a common mechanism for rapid adaptive changes during speciation, particularly in cases that present strong selective pressures on behavioral characters.

Animals↗
PubMed2004

Amyloid precursor protein mRNA levels in Alzheimer's disease brain.

Insoluble beta-amyloid deposits in Alzheimer's disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls (p=0.002). There was no change in the mRNA levels of KPI-(APP 695) (p=0.898). Therefore, whilst KPI-mRNA levels remained stable the KPI(+) species increased specifically in the AD brains.

Adult↗
PubMed2003

Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis.

BACKGROUND: RNA expression profiling can provide hints for the selection of candidate susceptibility genes, for formulation of hypotheses about the development of a disease, and/or for selection of candidate gene targets for novel drug development. We measured messenger RNA expression levels of 16 candidate genes in brain samples from 55 schizophrenia patients and 55 controls. This is the largest sample so far used to identify genes differentially expressed in schizophrenia brains. METHODS: We used a sensitive real-time polymerase chain reaction methodology and a novel statistical approach, including the development of a linear model of analysis of covariance type. RESULTS: We found two genes differentially expressed: monoamine oxidase B was significantly increased in schizophrenia brain (p =.001), whereas one of the serotonin receptor genes, serotonin receptor 2C, was significantly decreased (p =.001). Other genes, previously proposed to be differentially expressed in schizophrenia brain, were invariant in our analysis. CONCLUSIONS: The differential expression of serotonin receptor 2C is particularly relevant for the development of new atypical antipsychotic drugs. The strategy presented here is useful to evaluate hypothesizes for the development of the disease proposed by other investigators.

Cerebral Cortex↗
PubMed2003

An optimistic view for quantifying mRNA in post-mortem human brain.

Quantitative human mRNA data are derived from post-mortem or biopsied tissue. RNA degradation, poor replication, a large mRNA variance and confounding factors such as brain pH and age of death are often cited, however, as objections to the data's reliability. A central question is whether post-mortem human mRNA can be treated as a statistically ordered system. TaqMan real-time RT-PCR was used to measure seven mRNAs in 513 cortical samples taken from 90 Alzheimer's disease and 81 control brains. Despite a high mRNA variance strong correlations were found between the mRNA transcripts in a single brain. Where a brain has a high/low level of one mRNA, the same brain invariably has a high/low level of other mRNAs; correlated order is present and allows removal of that source of variation common to all genes. Although levels of mRNA are highly variable between subjects (>1000-fold), quantitative order is present in post-mortem human mRNA, allowing effects due to pathology or gender to be isolated and tested for significance.

Aged↗
PubMed2003

Beta-secretase (BACE) and GSK-3 mRNA levels in Alzheimer's disease.

Beta-secretase (BACE) and glycogen synthase kinase (GSK 3) are two enzymes thought to play a role in Alzheimer's disease. We extracted mRNA from 90 Alzheimer and 81 control brains. Levels of mRNA were quantified for BACE and GSK 3 with TaqMan real-time RT-PCR. We found no change in the Alzheimer's disease brains relative to controls for either the BACE or the GSK 3alpha mRNA levels.

Alzheimer Disease↗
PubMed2003

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Bipolar Disorder↗
PubMed2002

The quantification of gene expression in an animal model of brain ischaemia using TaqMan real-time RT-PCR.

Expression levels of mRNA are commonly measured as a ratio of test to reference gene. The assumption is that reference genes such as beta-actin or cyclophilin are unaffected by treatment and act as steady-state controls. TaqMan real-time RT-PCR was used to test these assumptions in a rat model of cerebral ischaemia (tMCAO). Following measurement of 24 genes, we show that reference genes in this animal model fail the criteria for steady-state controls. Neuronal loss, glial proliferation and an influx of leukocytes into the lesioned brain result in major disturbance to cell populations. The mRNA for reference genes, as for test genes, reflects these changes. Specific mRNA levels vary according to the choice of reference gene to which they are normalised. In the process of resolving reference gene issues, mRNA increases were discovered for leukaemia inhibitory factor, nestin and galanin in rat brain hemispheres affected by ischaemia. Results are reported for a further 21 genes and mathematical and statistical methods are described that allow in this study fraction-fold changes in mRNA to be detected.

Animals↗
PubMed2002

Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders.

Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.

Alleles↗
PubMed2002

Analysis of gene expression in the rat hippocampus using Real Time PCR reveals high inter-individual variation in mRNA expression levels.

In mammals, gene transcription is a step subjected to tight regulation mechanisms. In fact, changes in mRNA levels in the central nervous system (CNS) can account for numerous phenotypic differences in brain function. We performed a high-resolution analysis of mRNA expression levels for 37 genes selected from a normal rat hippocampus cDNA library. mRNA amounts were quantified using a Real Time PCR SYBR Green assay. We found that, in general, individuals from an inbred rat population (n = 20) have shown 2-3 times differences in the basal level of expression of the genes analyzed. Up to several fold differences among individuals were observed for certain genes. These inter-individual differences were obtained after correction for the different amounts of mRNA in each sample. Power calculations were performed to determine the number of individuals required to detect reliable differences in expression levels between a control and an experimental group. These data indicated that, depending on the variability of the candidate gene selected, it was necessary to analyze from five to 135 individuals in each group to detect differences of 50% in the levels of mRNA expression between two groups investigated. The comparison of mRNA abundance from different genes revealed a wide range of expression levels for the 37 genes, showing a 26,000-fold difference between the highest and lowest expressed gene.

Animals↗