The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia.

The synaptosomal-associated protein of 25 kDa (SNAP-25) is an essential component of the core complex that mediates presynaptic vesicle trafficking. Thus, SNAP-25 is directly involved in the release of neurotransmitters. Quantitative alterations of SNAP-25 expression have been reported in brain regions and cerebrospinal fluid (CSF) of schizophrenics and in haloperidol treated rats. This observed altered expression may be influenced by genetic variants of SNAP-25. We hypothesized that polymorphisms of the SNAP-25 gene (sites DdeI, MnlI and TaiI in the 3'UTR) are associated with antipsychotic drug response and induced weight gain. A sample of 59 patients with prior suboptimal response to antipsychotic treatment and diagnosed with DSM-IV schizophrenia or schizoaffective disorder was examined. Patients were administered clozapine, haloperidol, olanzapine or risperidone for up to 14 weeks. Clinical response was defined as the difference between the baseline and the endpoint total scores on the Positive and Negative Syndrome Scale (PANSS). Weight was assessed at baseline and at study endpoint. ANOVA revealed that the MnlI and TaiI polymorphisms were associated with response (F[2,53] = 4.57, p = 0.01 and F[2,52] = 3.53, p = 0.03) and with weight gain (F[2,52] = 4.28, p = 0.01 and F[2,51] = 3.38, p = 0.04). When covariates were included, the MnlI polymorphism remained significantly associated with changes of PANSS scores, but not with weight gain. The DdeI polymorphism was not associated with response or weight gain. These findings suggest that SNAP-25 gene variants affect clinical response in patients with prior poor response to antipsychotics. Weight changes do not seem to be associated with polymorphism of the SNAP-25 gene, however, replication in independent samples is warranted.

NOTCH4 gene haplotype is associated with schizophrenia in African Americans.

BACKGROUND: The goal of this study was to investigate the relationship between the NOTCH4 gene and schizophrenia in African American (AA) and European American (EA) subjects. METHODS: Two single nucleotide polymorphisms (SNPs) at the NOTCH4 locus were genotyped in 123 AA schizophrenia patients, 223 EA schizophrenia patients, 85 AA healthy control subjects, and 211 EA healthy control subjects. The specific markers studied were -1725T/G and -25T/C. Comparisons of allele and haplotype frequencies between patients and control subjects were performed with the chi-square test, the Fisher's Exact Test, and CLUMP software. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. RESULTS: The haplotype -1725G/-25T associates to schizophrenia in AA subjects (p =.0008), but not in EA subjects. Alleles -1725G and allele -25T are in positive LD both in AAs and EAs. Allele and haplotype frequencies differ significantly between AAs and EAs. CONCLUSIONS: The haplotype -1725G/-25T at the NOTCH4 locus, which results from SNPs of NOTCH4 that are in LD, may increase susceptibility to schizophrenia in AAs. Any effect of this locus on risk for schizophrenia is population-specific.

Association between schizophrenia and the syntaxin 1A gene.

BACKGROUND: Both microarray and candidate molecule studies have demonstrated that protein and mRNA expression of syntaxin and other genes involved in synaptic function are altered in the cerebral cortex of patients with schizophrenia. METHODS: Genetic association between polymorphic markers in the syntaxin 1A gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 238 nuclear families. RESULTS: In the family-based sample, a significant genetic association was found between schizophrenia and one of the four single nucleotide polymorphisms (SNPs) tested: an intron 7 SNP (transmission disequilibrium test [TDT] chi(2) = 5.898; df = 1; p =.015, family-based association test [FBAT] z = 2.280, p =.023). When the results for the TDT and case-control analyses were combined, the association was stronger (n = 430; z(c) = 2.859; p =.004). Haplotype analysis supported the association with several significant values that appear to be driven by the intron 7 SNP. CONCLUSIONS: The results should be treated with caution until replicated, but this is the first report of a genetic association between syntaxin 1A and schizophrenia.

Altered expression of lipid metabolism and immune response genes in the frontal cortex of suicide completers.

BACKGROUND: Studies investigating the association between low cholesterol and suicidality have generated a range of ideas about how cholesterol might play a role in influencing suicide risk, extending studies to other aspects of lipid metabolism, as well as immune response, in relation to suicide. METHODS: We performed large-scale microarray gene expression analysis using the Affymetrix HG-U133 chipset and focused our investigation on the expression profile of genes related to lipid metabolism and immune response in post-mortem brains from suicide completers and comparison subjects. We used tissue from three regions of the frontal cortex (Brodmann areas (BA) 8/9, 11, and 47) from 22 male suicide completers, 15 of whom were diagnosed with major depressive disorder, and 13 male comparison subjects. RESULTS: Fatty acid desaturase (FADS1), leptin receptor (LEPR), phosphoinositide-3-kinase (class 2 alpha; PIK3C2A) and stearoyl-CoA desaturase (SCD) were consistently down-regulated in all three regions of the frontal cortex of depressed suicides compared to comparison subjects, and were among the genes for which significant correlations were observed between our microarray and real-time PCR data. LIMITATIONS: Given the absence of a non-suicidal depressed comparison group in this study, it cannot be ascertained whether the gene expression changes identified are associated with depression or suicide. CONCLUSIONS: Our findings suggest a role for lipid metabolism and immune response genes in depressed suicide completers and lend further support to the relationship between lipid metabolism and suicidality.

Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers.

CONTEXT: Although most of the effort to understand the neurobiology of depressive states and suicide has focused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. A truncated variant of the tropomyosin-related kinase B (TrkB.T1) is expressed in astrocytes, and brain-derived neurotrophic factor-TrkB signaling has been linked to mood disorders. OBJECTIVE: To test the hypothesis that TrkB.T1 expression is downregulated in suicide completers and that this downregulation is mediated by an epigenetic process. DESIGN: Postmortem case-control study. Patients, Setting, and MAIN OUTCOME MEASURES: Thirty-nine French Canadian men underwent screening at the Douglas Hospital Research Institute using the HG-U133 plus 2 microarray chip. Nine frontal cortical regions and the cerebellum were assessed using a microarray screening approach for extreme expression differences across subjects and a conventional screening approach. Results were validated by quantitative polymerase chain reaction and Western blot analyses. Animal experiments were performed to control for drug and alcohol effects. Genetic and epigenetic studies were performed by means of direct sequencing and bisulfite mapping. RESULTS: We found that 10 of 28 suicide completers (36%) demonstrated significant decreases in different probe sets specific to TrkB.T1 in Brodmann areas 8 and 9. These findings were generalizable to other frontal regions but not to the cerebellum. The decrease in TrkB expression was specific to the T1 splice variant. Our results were not accounted for by substance comorbidity or by reduction in astrocyte number. We found no effect of genetic variation in a 2500-base pair promoter region or at relevant splice junctions; however, we detected an effect of methylation state at particular CpG dinucleotides on TrkB.T1 expression. CONCLUSION: A reduction of TrkB.T1 expression in the frontal cortex of a subpopulation of suicide completers is associated with the methylation state of the promoter region.

Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression.

BACKGROUND: Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations. METHODOLOGY/PRINCIPAL FINDINGS: We performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data. CONCLUSIONS/SIGNIFICANCE: The observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.

The genetics of suicide: a critical review of molecular studies.

Genetic epidemiology research has shown that genes contribute to suicide risk. Unfortunately, the first 30 years of candidate-based association studies have provided little information about the specific genetic contributors. This article reviews genetic association studies of suicidal phenotypes published to date. Possible theoretical, methodological, and operational challenges accounting for the modest success of association studies in the field are also discussed. The authors conclude that future research may benefit from using a more systematic and comprehensive selection of candidate genes and variants, examining gene-environment and gene-gene interactions, and investigating higher-order moderators.

Confirmation of region-specific patterns of gene expression in the human brain.

The human brain is divided and categorized in different ways, yet a molecular genetic approach to region specificity does not exist. Using data from 12 healthy control subjects across 18 brain regions, we performed a microarray analysis using both the HG-U133AB and HG-U133 plus 2 chips for each subject to determine molecular targets showing region specificity. Using a previously published data as our guide, we confirm SIX3, GPR6, SH3RF2, and hSyn as molecular markers of the nucleus accumbens and gamma-aminobutyric-acid A receptor alpha-6, Nik-related kinase, and eomesodermin as molecular markers of the cerebellum.