36 research outputs found

    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

    Association of <i>DCKL1</i> genetic variants with psychiatric and cognitive traits.

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    <p>Markers are ordered from 5′ to 3′ of the gene, anti-sense to the reference sequence. <b>A.</b> Representation of the genomic region covered and of 6 <i>DCLK1</i> transcripts (from top to bottom: <i>DCL</i>, <i>CARP</i>, 2 short variants and 2 long variants). In addition to alternative start sites, the transcripts can be alternatively spliced for part of exon 9, for exon 19 and in the 3′UTR. <b>B.</b> All markers showing nominal association to psychiatric traits in this study or to cognitive traits in our previous study <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035424#pone.0035424-LeHellard1" target="_blank">[16]</a> are displayed. Color code: yellow, P-value between 0.05 and 0.001; orange, P-value between 0.001 and 0.0001; red, P-value<0.0001; white, P-value>0.05; grey, marker not tested in this sample. The markers used in the cross-phenotype analyses are highlighted in red. <b>C.</b> LD between the markers used in the cross-phenotype analyses, and the markers associated with cognitive traits in our previous study <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035424#pone.0035424-LeHellard1" target="_blank">[16]</a>. LD is displayed using a r<sup>2</sup> scale ranging from r<sup>2</sup> = 1 in black to r<sup>2</sup> = 0 in white.</p

    Testing gene sets associated with normal neurocognitive variation for enrichment of association with schizophrenia.

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    <p><i>q</i>-value, obtained from 3 GSEA runs with 1,000 permutations each). The maximum standard deviation from the average <i>q</i>-value was 0.06. Sets that passed the enrichment threshold (<i>p</i>-value≤0.05, FDR <i>q</i>-value≤0.25) were tested for validation using random mimic sets (see Table S4 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081052#pone.0081052.s001" target="_blank">File S1</a>).<sup></sup> For each GWAS dataset the 5 most enriched candidate sets are shown. The rank position (R) of the gene set within the total number of gene sets tested was determined by the average false discovery rate (</p><p>% of the random sets (i.e. validated sets).<sup>a</sup> indicates sets that were more enriched than 98</p><p><sup>b</sup> indicates sets that did not pass the enrichment threshold but were among the 5 most enriched in the corresponding sample.</p><p>“n.e.”. Visuospatial attention.1 – Visuospatial attention task with valid cue to the location of the visual target; Visuospatial attention.3 – Visuospatial attention task with neutral cue to the location of the visual target. The number after each gene set name represents the number of genes within that set (e.g. the Colour-word interference −25 set contains the top 25 genes within the colour-word interference ranking list of genes).<sup></sup> Sets that did not pass the enrichment threshold and ranked outside the top 5 are indicated by </p

    Analysis of object recognition memory in Csmd1 KO and WT mice.

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    <p>(A and B) Object contacts in the first and second trial of exposure to novel and familiar objects demonstrated increased contact counts for <i>Csmd1</i> KO mice (P-value<0.05). (B and C) Discrimination and preference analysis demonstrated no effect of <i>Csmd1</i> on object recognition. Abbreviation: n.s., not significant; asterisk, statistically significant (<i>P</i>-value<0.05).</p

    Testing gene sets associated with normal neurocognitive variation for enrichment of association with bipolar disorder.

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    <p><i>q</i>-value, obtained from 3 GSEA runs with 1,000 permutations each). The maximum standard deviation from the average <i>q</i>-value was 0.07. Sets that passed the enrichment threshold (<i>p</i>-value≤0.05, FDR <i>q</i>-value≤0.25) were tested for validation using random mimic sets (see Table S4 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081052#pone.0081052.s001" target="_blank">File S1</a>).<sup></sup> For each GWAS dataset, the 5 most enriched candidate sets are shown. For the German dataset, the 14 most enriched sets are presented to show the overlap with the other datasets. The rank position (R) of the gene set within the total number of gene sets tested is determined by the average false discovery rate (</p><p>% of the random sets (i.e. validated sets).<sup>a</sup> indicates sets that were more enriched than 98</p><p><sup>b</sup> indicates sets that did not pass the enrichment threshold but were among the 5 most enriched in the corresponding sample.</p><p>“n.e.”. Visuospatial attention.1 – Visuospatial attention task with valid cue to the location of the visual target; Visuospatial attention.3 – Visuospatial attention task with neutral cue to the location of the visual target. The number after each gene set name represents the number of genes within that set (e.g. the Colour-word interference −25 set contains the top 25 genes within the colour-word interference ranking list of genes).<sup></sup> Sets that did not pass the enrichment threshold and ranked outside the top 5 are indicated by </p><p><i>p-</i>value of zero (0.0) indicates an actual <i>p</i>-value of less than 1/number-of-permutations.<sup></sup> A reported </p

    Genetic Sources Influencing Relational Complexity (RC) Underpin Intelligence and Covariation Between Reasoning and Working Memory.

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    <p>In this Cholesky decomposition [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123886#pone.0123886.ref041" target="_blank">41</a>], additive genetic factors are designated A<sub>1</sub>-A<sub>4</sub>, and non-shared environmental factors E<sub>1</sub>-E<sub>4</sub> (dashed lines indicate non-significant pathways). Heritability (<i>h<sup>2</sup></i>) is shown for each trait. Parameter estimates are standardised such that when squared they indicate the percentage of variance accounted for (shown with 95% confidence intervals). Variable order was chosen to examine (i) the contribution of sources influencing RC (i.e. A<sub>1</sub>, E<sub>1</sub>) to the covariation between reasoning and working memory, and (ii) if sources influencing IQ added to this covariation independently of RC. For greater detail see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123886#pone.0123886.s002" target="_blank">S2 Text</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123886#pone.0123886.s001" target="_blank">S1 Fig</a> (focussing on covariation between RC and IQ) and S2 (showing alternative variable orders for the quadrivariate Cholesky). Note that unless there are qualitative sex differences, the order of traits in a Cholesky decomposition does not change measure of fit (or conclusion).</p

    Neuropsychological Deficits in Mice Depleted of the Schizophrenia Susceptibility Gene <i>CSMD1</i>

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    <div><p>Recent meta-analyses of schizophrenia genome-wide association studies (GWASs) have identified the <i>CUB and SUSHI multiple domains 1</i> (<i>CSMD1</i>) gene as a statistically strong risk factor. CSMD1 is a complement control-related protein suggested to inhibit the classical complement pathway, being expressed in developing neurons. However, expression of <i>CSMD1</i> is largely uncharacterized and relevance for behavioral phenotypes is not previously demonstrated. Here, we assess neuropsychological behaviors of a <i>Csmd1</i> knockout (KO) mouse in a selection of standard behavioral tests. Deregulation of neuropsychological responses were observed in both the open field and the elevated plus maze tests, in which KO mice spent 55% and 33% less time than WT littermate mice in open areas, respectively. Altered behaviors were also observed in tail suspension and to higher acoustic stimuli, for which <i>Csmd1</i> KO mice showed helplessness and moderate increase in startle amplitude, respectively. Furthermore, <i>Csmd1</i> KO mice also displayed increased weight-gain and glucose tolerance, similar to a major phenotype of the metabolic syndrome that also has been associated to the human <i>CSMD1</i> locus. Consistent with a role in the control of behaviors, <i>Csmd1</i> was found highly expressed in the central nervous system (CNS), and with some expression in visceral fat and ovary, under tissue-specific control by a novel promoter-associated lncRNA. In summary, disruption of <i>Csmd1</i> induces behaviors reminiscent of blunted emotional responses, anxiety and depression. These observations suggest an influence of the <i>CSMD1</i> schizophrenia susceptibility gene on psychopathology and endophenotypes of the negative symptom spectra.</p></div

    GSEA of differentially expressed cortical genes in psychiatric disorders and non-psychiatric phenotypes.

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    <p>GSEA was used to analyse the differentially expressed cortical genes, as gene sets, for enrichment of association signal in three different BP GWASs (a German sample, the Norwegian TOP sample and the British WTCCC BP sample <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Cichon1" target="_blank">[20]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Djurovic1" target="_blank">[41]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-WTCCC1" target="_blank">[42]</a>), three SCZ GWASs (the Norwegian TOP sample, the German part of a combined German-Dutch SCZ GWAS and a Danish sample <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Rietschel1" target="_blank">[19]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Athanasiu1" target="_blank">[43]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Ingason1" target="_blank">[44]</a>) and six non-psychiatric phenotypes (from WTCCC; CD: Crohn's disease, CHD: coronary heart disease, HT: hypertension, RA: rheumatoid arthritis, T1D: type 1 diabetes and T2D: type 2 diabetes, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-WTCCC1" target="_blank">[42]</a>). The analysis was based on extraction of modified Sidak's minimum <i>P</i>-values <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Saccone1" target="_blank">[45]</a>, as implemented in LDsnpR. FDR q-value<0.1 was set as cut-off value for significant enrichment.</p>*<p>: One FMCx gene was not represented in the data set.</p>**<p>: Two FMCx genes were not represented in the data set.</p

    <i>Csmd1</i> RNA and protein expression in <i>Csmd1</i> knock-out and wild-type mice.

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    <p>(A) Schematic representation of the KO-strategy. A 1 kb genomic region (white lines) of exon1/intron1 was replaced with a selection cassette (grey box). (B) Expression of <i>Csmd1</i> mRNA measured by QPCR in an adult mouse tissue panel. <i>Csmd1</i> is predominantly expressed in brain tissues as compared to peripheral tissues. The highest expression level was identified in areas of the cortex. (C) Depletion of <i>Csmd1</i> mRNA in the cortex was documented by two exon-exon specific QPCR assays. Transcription of exon 1–2 was depleted, while about 20% residual expression could be observed when amplifying exon 32–33. KO mice lacked a protein band of expected size (389 KDa, arrow), as demonstrated by immunoblotting. Signals of lower molecular weight are indicated (a and b). (D) Mapping of RNA-seq reads to the <i>Csmd1</i> locus. RNA sequencing of cortex is shown for 4wild-type (green) and 4 <i>Csmd1</i> KO (red) mice (transcript scale: 0–150 reads). Coverage signals of modified nucleosomes (H3K4me3, H3K4me1 and H3K27Ac) and polymerase-2 binding profiles are shown for the mouse cortex. The 1 kb deleted sequence of <i>Csmd1</i> is highlighted in yellow (upper panel) and blue (lower panel). No RNA reads were mapped to the deleted genomic region in the KO mice. Abbreviations: Cx, cortex; VCx, visual cortex; FCx, frontal cortex; Hipp, hippocampus; Hyp, hypothalamus; Ob, olfactory bulb; Cer, cerebellum; Visc. Fat, visceral fat.</p
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