28 research outputs found

    Mapping genomic loci implicates genes and synaptic biology in schizophrenia

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    Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

    PACAP Protects Adult Neural Stem Cells from the Neurotoxic Effect of Ketamine Associated with Decreased Apoptosis, ER Stress and mTOR Pathway Activation

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    <div><p>Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs <i>via</i> AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine <i>via</i> the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, <i>via</i> neurogenesis normalization.</p></div

    PACAP counteracts ketamine induced mTOR activation.

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    <p>NSCs were plated as single cells and treated with 400 μM alone or with 100 nM PACAP and 400 μM ketamine. Cells were treated as indicated and after 1, 2, 6 and 24 hour incubation cells were harvested for Western blot experiments <b>(A)</b>. Cells were treated as indicated and incubated for 1 and 2 hours and harvested for Western blot experiments <b>(B)</b>. To obtain quantitative measurements p-mTOR were normalized against total-mTOR. Data are shown as mean ±SEM (A, n = 4–8; B, n = 3–5). Kruskal-Wallis followed by Dunn’s test or Fisher LSD test was used. Differences were considered significant at P<0.05. * denotes P<0.05 compared with control, # denotes P<0.05 compared to ketamine + 1 hour or ketamine + 2 hours.</p

    Gene expression data of the Allen Human Brain Atlas were mapped onto the 12 genetically based cortical regions in the MR space.

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    <p>A) Resulting volume registration between FreeSurfer surface (fsaverage) and Allen brain MNI coordinates displayed as a point cloud, with a slice of the MRI imaging at the bottom (colin27). B) After the volume registration, gene expression data points are mapped to FreeSurfer surface vertices by assigning each surface vertex the gene expression of the closest (Euclidean distance) Allen brain data point using nearest neighbor interpolation. If two vertices have the same closest Allen brain data point, they belong to the same patch and the patch id is displayed as color. Thus, the color patches illustrate the local density of data points. The color patches with similar sizes across the cortex represent an even distribution of Allen brain data points and their surface correspondences. Colors of the dots in both (A) and (B) panels represent cortical regions to which they were assigned, corresponding to the color schemes in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006143#pgen.1006143.g001" target="_blank">Fig 1B</a>.</p

    Distribution of CNV patterns that were significantly overrepresented in one haplogroup only.

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    <p>Each part of the figure shows the graphical representation of the first two eigenvectors after PCA analysis A. The figure shows PCA values for individuals with P3 dupl. significantly overrepresented in haplogroup E-M96. B. Individuals with b2/b3 del. significantly overrepresented in haplogroup NO-M214(xM175). C. Individuals with gr/gr del. (c8) significantly overrepresented in haplogroup D-M174. This CNV is also present in other haplogroups. D. Individuals with gr/gr dupl. (c9) + distal dupl. significantly overrepresented in haplogroup J-P256.</p

    qPCR validation of the newly discovered P6 duplication.

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    <p>Amplification plots for a female (green), a control male (purple) and a male with P6 dupl. (blue) are shown for markers RH38681 (A), sY1081 (B) and sY933 (C). D. Intensity signal plot (Log 2 ratio) for an individual with P6 dupl. showing that markers sY1081 and sY933 are positioned within the duplicated region, while RH38681 is located outside.</p

    miRNA minor allele frequencies in three Scandinavian samples, allele counts and related p-values for allelic association.

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    <p>Monomorphic miRNA SNPs: hsa-let-7a-1 (rs7847425),hsa-let-7a-3 (rs9627620),hsa-mir-100 (rs11821130),hsa-mir-125a (rs12975333),hsa-mir-126 (rs7846876),hsa-mir-191 (rs11706445),hsa-mir-221 (rs7050391),hsa-mir-23b (rs3802448)and hsa-mir-99b (rs8112073). NA: Not available, Ex: Excluded, NC: Not calculated, DK: Denmark, SE: Sweden, NO: Norway, CMH: Cochran-Mantel-Haenszel test for 2×2×K stratified tables and BD: Breslow-Day test of homogeneity of odds ratio. <sup>1</sup>The major allele is give prior to the minor allele <sup>2</sup>P-values obtained from chisq exact test for Hardy-Weinberg Proportions. <sup>3</sup>P-values from chisq test for differences in allele proportions.</p