Homo sapiens
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PROVIDER: PRJNA254737 | ENA |
REPOSITORIES: ENA
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Project description:22q11.2 Deletion Syndrome (22q11DS) represents one of the most common known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes. Eighty percent of 22q11DS individuals (n=37) carried the typical 3 Mb deletion, with significant variability in the deletion characteristics in the remainder of the sample (n=9). Both analysis of differential expression and weighted gene coexpression network analysis (WGCNA) identified peripheral changes in gene expression related to psychotic symptom expression in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. Remarkably, this 22q11DS psychosis module was significantly enriched for brain-expressed genes, was not related to antipsychotic medication use, and showed significant overlap with transcriptional changes occurring in idiopathic schizophrenia in an independent dataset. In those with 22q11DS-ASD, both differential expression and WGCNA analyses pointed towards dysregulation of immune response pathways. The ASD-associated module showed overlap with a neuronal module enriched for known autism susceptibility genes identified in brain transcriptome data from individuals with idiopathic autism. These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD, warranting their further investigation in idiopathic illness. Participants. Forty-six patients with a molecularly confirmed diagnosis of a 22q11.2 deletion and 66 controls (24 unrelated controls and 42 first-degree relatives of 22q11DS patients) were recruited from an ongoing longitudinal study. Comparative Genomic Hybridization Arrays. To characterize the boundaries of the 22q11.2 deletion, we designed a custom NimbleGen 12*135 HX12 array. Microarray-based gene expression analysis. Whole-genome transcriptional profiling was performed using Illumina Human HT-12 microarrays.Gene ontology annotation was performed using DAVID (http://david.abcc.ncifcrf.gov/) and pathway analysis was performed by using the Functional Analysis Annotation tool in the Ingenuity Pathways Analysis (IPA) software (Ingenuity Systems, www.ingenuity.com). Because the healthy control group included parents of 22q11DS patients, there were significant age differences between groups (Table 1, p<.001); thus, we corrected for age in all analyses.Weighted Gene Co-expression Network Analysis (WGCNA). We conducted WGCNA, a systems biology approach used to identify networks of co-expressed genes in relation to phenotypic data, using the R package. Phenotypic traits examined within the 22q11DS group included: categorical and dimensional indicators of psychosis (i.e. psychosis diagnosis and SIPS psychotic symptom severity score), ASD, and gender. For modules that showed a statistically significant relationship with any phenotypic trait (p<.05), GO analyses and IPA were conducted. Validation with published datasets. In order to validate our gene expression and WGCNA results, we overlapped gene lists obtained from microarray differential expression analysis for 22q11DS vs. Controls,
2015-09-01 | E-GEOD-59216 | biostudies-arrayexpress
Project description:22q11.2 Deletion Syndrome (22q11DS) represents one of the most common known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes. Eighty percent of 22q11DS individuals (n=37) carried the typical 3 Mb deletion, with significant variability in the deletion characteristics in the remainder of the sample (n=9). Both analysis of differential expression and weighted gene coexpression network analysis (WGCNA) identified peripheral changes in gene expression related to psychotic symptom expression in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. Remarkably, this 22q11DS psychosis module was significantly enriched for brain-expressed genes, was not related to antipsychotic medication use, and showed significant overlap with transcriptional changes occurring in idiopathic schizophrenia in an independent dataset. In those with 22q11DS-ASD, both differential expression and WGCNA analyses pointed towards dysregulation of immune response pathways. The ASD-associated module showed overlap with a neuronal module enriched for known autism susceptibility genes identified in brain transcriptome data from individuals with idiopathic autism. These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD, warranting their further investigation in idiopathic illness.
2015-09-01 | GSE59216 | GEO
Project description:22q11.2 deletion syndrome (22q11DS) is a common cause of developmental neuropsychiatric disorders, including psychosis, autism and epilepsy. This highly penetrant genetic syndrome provides a unique opportunity to mitigate the challenges raised by the heterogeneity of complex mental disorders and to identify specific neuronal phenotypes. Here, we generated induced pluripotent stem cells from subjects carrying a 3 Mb deletion at the 22q11.2 locus and from controls and differentiated these cells in vitro into three-dimensional organoid resembling the developing cerebral cortex. We performed single-cell RNA-sequencing to establish the reliability and reproducibility of cortical organoid differentiation in 22q11DS.
2020-07-08 | GSE145122 | GEO
Project description:Individuals with 22q11.2 Deletion Syndrome (22q11.2 DS) are a specific high-risk group for developing schizophrenia (SZ), schizoaffective disorder (SAD) and autism spectrum disorders (ASD). Several genes in the deleted region have been implicated in the development of SZ, e.g., PRODH and DGCR8. However, the mechanistic connection between these genes and the neuropsychiatric phenotype remains unclear. To elucidate the molecular consequences of 22q11.2 deletion in early neural development, we carried out RNA-seq analysis to investigate gene expression in differentiating human neurons derived from induced pluripotent stem cells (iPSCs) of 22q11.2 DS SZ and SAD patients. Eight cases (ten iPSC-neuron samples in total including duplicate clones) and seven controls (nine in total including duplicate clones) were subject to RNA sequencing. Using a systems level analysis, differentially expressed genes/gene-modules and pathway of interests were identified. We observed ~2-fold reduction in expression of almost all genes in the 22q11.2 region in SZ (37 genes reached p-value < 0.05, 36 of which reached a false discovery rate < 0.05). Outside of the deleted region, 745 genes showed significant differences in expression between SZ and control neurons (p<0.05). Function enrichment and network analysis of the differentially expressed genes uncovered converging evidence on abnormal expression in key functional pathways, such as apoptosis, cell cycle and survival, and MAPK signaling in the SZ and SAD samples.
2013-11-01 | GSE46562 | GEO
Project description:The 22q11.2 deletion syndrome (22q11.2DS) is the most common copy number variant (CNV)-associated syndrome, leading to congenital and neuropsychiatric anomalies. Patient-derived, induced pluripotent stem cell (iPS) models have provided important insight into the mechanisms of phenotypic features of this condition. However, patient-derived iPSC models may harbor underlying genetic heterogeneity that can confound analysis of pathogenic CNV effects. Furthermore, the ~1.5 Mb “A-B” deletion at this locus is inherited at higher frequency than the more common ~2.7 Mb “A-D” deletion, but remains under-studied due to lack of relevant models. To address these issues, here we leveraged a CRISPR-based strategy in Cas9-expressing iPS cells to engineer novel isogenic models of the 22q11.2 “A-B” deletion. After in vitro differentiation to excitatory neurons, integrated transcriptomic and cell surface proteomics identified deletion-associated alterations in surface adhesion markers. Furthermore, implantation of iPS-derived neuronal progenitor cells into the cortex of neonatal mice found decreased proliferation and accelerated neuronal maturation within a relevant microenvironment. Taken together, our results suggest potential pathogenic mechanisms of the 22q11.2 “A-B” deletion in driving neuronal and neurodevelopmental phenotypes. We further propose that the isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.
2023-05-11 | PXD032075 | Pride
Project description:Among the fundamental unresolved questions in psychiatry is why symptoms of psychosis, such as auditory hallucinations in schizophrenia, fail to appear until early adulthood. Here we report that in mouse models of 22q11.2 deletion syndrome (22q11DS), a leading genetic cause of schizophrenia, synaptic transmission at thalamocortical inputs to the auditory cortex becomes disrupted later in life, thereby recapitulating the adult onset of psychosis. Age-dependent disruption of thalamocortical synaptic transmission in 22q11DS is mediated by dopamine receptor Drd2-targeting microRNA miR-338-3p, which is enriched in the thalamus but becomes depleted due to haploinsufficiency of the microRNA-processing 22q11DS gene Dgcr8. Deletion/knockdown of miR-338-3p causes the Drd2 increase in the auditory thalamus and abnormal sensitivity of 22q11DS thalamocortical inputs to antipsychotics, replicates auditory synaptic and behavioral abnormalities in 22q11DS, and eliminates age dependence of these auditory deficits. These results suggest that miR-338-3p mediates the pathogenic mechanism of 22q11DS-related psychosis and controls its late onset.
2016-10-10 | GSE73981 | GEO
Project description:The ever-growing compendium of genetic variants associated with human pathologies demands novel methods to study genotype-phenotype relationships in complex tissues in high-throughput. Here, we introduce AAV-mediated direct in vivo single-cell CRISPR screens, termed AAV-Perturb-seq, a tunable and broadly applicable method for high-throughput and high-resolution phenotyping of genetic perturbations in vivo. We applied AAV-Perturb-seq using gene editing and transcriptional inhibition to systematically dissect the phenotypic landscape underlying 22q11.2 deletion syndrome genes in the adult mouse brain prefrontal cortex. We identified three 22q11.2-linked genes involved in known and novel pathways orchestrating neuronal functions in vivo that explain approximately 40% of the transcriptional changes observed in a 22q11.2 deletion mouse model. Our findings suggest that the 22q11.2 deletion syndrome transcriptional phenotype found in mature neurons may in part be due to the broad dysregulation of a class of disease susceptibility genes important for dysfunctional RNA processing and synaptic function. Our work establishes a flexible and scalable direct in vivo method to facilitate causal understanding of biological and disease mechanisms with potential applications to identify genetic interventions and therapeutic targets for treating disease.
2023-09-20 | GSE236519 | GEO
Project description:Background: The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with highly variable phenotypic manifestations, even though most patients present the typical 3 Mb microdeletion, usually affecting the same ~ 106 genes. One of the genes affected by this deletion is DGCR8, which plays a crucial role in miRNA biogenesis. Therefore, the haploinsufficiency of DGCR8 due to this microdeletion can alter the modulation of the expression of several miRNAs involved in a range of biological processes. Results: In this study, we used next-generation sequencing to evaluate the miRNAs profiles in the peripheral blood of 12 individuals with typical 22q11DS compared to 12 healthy matched controls. We used the DESeq2 package for differential gene expression analysis and the DIANA-miTED dataset to verify the expression of differentially expressed miRNAs in other tissues. We used miRWalk to predict the target genes of differentially expressed miRNAs. Here, we described two differentially expressed miRNAs in patients compared to controls: hsa-miR-1304-3p, located outside the 22q11.2 region, upregulated in patients, and hsa-miR-185-5p, located in the 22q11.2 region, which showed downregulation. Expression of miR-185-5p is observed in tissues frequently affected in patients with 22q11DS, and previous studies have reported its downregulation in individuals with 22q11DS. hsa-miR-1304-3p has low expression in blood and, thus, needs more validation, though using a sensitive technology allowed us to identify differences in expression between patients and controls. Conclusions: Thus, lower expression of miR-185-5p can be related to the 22q11.2 deletion and DGCR8 haploinsufficiency, leading to phenotypic consequences in 22q11.2DS patients, while higher expression of hsa-miR-1304-3p might be related to individual genomic variances due to the heterogeneous background of the Brazilian population. Background: The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with highly variable phenotypic manifestations, even though most patients present the typical 3 Mb microdeletion, usually affecting the same ~ 106 genes. One of the genes affected by this deletion is DGCR8, which plays a crucial role in miRNA biogenesis. Therefore, the haploinsufficiency of DGCR8 due to this microdeletion can alter the modulation of the expression of several miRNAs involved in a range of biological processes. Results: In this study, we used next-generation sequencing to evaluate the miRNAs profiles in the peripheral blood of 12 individuals with typical 22q11DS compared to 12 healthy matched controls. We used the DESeq2 package for differential gene expression analysis and the DIANA-miTED dataset to verify the expression of differentially expressed miRNAs in other tissues. We used miRWalk to predict the target genes of differentially expressed miRNAs. Here, we described two differentially expressed miRNAs in patients compared to controls: hsa-miR-1304-3p, located outside the 22q11.2 region, upregulated in patients, and hsa-miR-185-5p, located in the 22q11.2 region, which showed downregulation. Expression of miR-185-5p is observed in tissues frequently affected in patients with 22q11DS, and previous studies have reported its downregulation in individuals with 22q11DS. hsa-miR-1304-3p has low expression in blood and, thus, needs more validation, though using a sensitive technology allowed us to identify differences in expression between patients and controls. Conclusions: Thus, lower expression of miR-185-5p can be related to the 22q11.2 deletion and DGCR8 haploinsufficiency, leading to phenotypic consequences in 22q11.2DS patients, while higher expression of hsa-miR-1304-3p might be related to individual genomic variances due to the heterogeneous background of the Brazilian population. Background: The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with highly variable phenotypic manifestations, even though most patients present the typical 3 Mb microdeletion, usually affecting the same ~ 106 genes. One of the genes affected by this deletion is DGCR8, which plays a crucial role in miRNA biogenesis. Therefore, the haploinsufficiency of DGCR8 due to this microdeletion can alter the modulation of the expression of several miRNAs involved in a range of biological processes. Results: In this study, we used next-generation sequencing to evaluate the miRNAs profiles in the peripheral blood of 12 individuals with typical 22q11DS compared to 12 healthy matched controls. We used the DESeq2 package for differential gene expression analysis and the DIANA-miTED dataset to verify the expression of differentially expressed miRNAs in other tissues. We used miRWalk to predict the target genes of differentially expressed miRNAs. Here, we described two differentially expressed miRNAs in patients compared to controls: hsa-miR-1304-3p, located outside the 22q11.2 region, upregulated in patients, and hsa-miR-185-5p, located in the 22q11.2 region, which showed downregulation. Expression of miR-185-5p is observed in tissues frequently affected in patients with 22q11DS, and previous studies have reported its downregulation in individuals with 22q11DS. hsa-miR-1304-3p has low expression in blood and, thus, needs more validation, though using a sensitive technology allowed us to identify differences in expression between patients and controls. Conclusions: Thus, lower expression of miR-185-5p can be related to the 22q11.2 deletion and DGCR8 haploinsufficiency, leading to phenotypic consequences in 22q11.2DS patients, while higher expression of hsa-miR-1304-3p might be related to individual genomic variances due to the heterogeneous background of the Brazilian population.
2025-02-23 | GSE289984 | GEO
Project description:Consequences of postnatal Tshz3 deletion: implications for autism spectrum disorder
| PRJNA662338 | ENA