The INO80E at 16p11.2 locus increases risk of schizophrenia in humans and induces schizophrenia-like phenotypes in mice
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ABSTRACT:
PROVIDER: PRJNA1156074 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30526400_1.fastq.gz | Fastqsanger.gz | |||
| SRR30526400_2.fastq.gz | Fastqsanger.gz | |||
| SRR30526401_1.fastq.gz | Fastqsanger.gz | |||
| SRR30526401_2.fastq.gz | Fastqsanger.gz | |||
| SRR30526394_1.fastq.gz | Fastqsanger.gz |
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Project description:Background Chromosome 16p11.2 is one of the most significant loci in the genome-wide association study (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies have been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized. Methods We performed expression quantitative trait loci (eQTL) and summary-data-based Mendelian randomization (SMR) analyses to identify schizophrenia risk genes in the 16p11.2 GWAS locus. We constructed the murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of Adeno-associated Virus (AAV), followed by behavioral assessments, dendritic spine analyses and RNA sequencing. Findings We identified significant associations between elevated INO80E mRNA expression in frontal cortex and risk of schizophrenia. The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviors, including increased anxiety behavior, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group. The neuronal sparse labeling assay showed that the density of mushroom spines in the pyramidal neurons of mPFC was significantly decreased in Ino80e-OE mice compared with control mice, accompanied by a notable increase in the density of stubby spines. Transcriptomic analysis in the mPFC revealed significant alterations in the mRNA levels of schizophrenia-related genes and processes related to synapses upon overexpressing Ino80e . Interpretation Our results suggest that upregulation of the Ino80e gene in mPFC may induce schizophrenia-like behaviors in mice, further supporting the hypothesis that INO80E is an authentic risk gene.
2024-10-01 | GSE276239 | GEO
Project description:The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2. The genome-wide transcript perturbations correlated with clinical endophenotypes of the CNV and were enriched for genes associated with ASD. We uncovered a significant correlation between copy number changes and expression levels of genes mutated in ciliopathies. Transcriptome profiles of lymphoblastoid cell lines of 50 16p11.2 deletion carriers, 31 16p11.2 duplication carriers and 17 controls.
2015-05-10 | E-GEOD-57802 | biostudies-arrayexpress
Project description:Background: Chromosomal 16p11.2 deletions and duplications are genomic disorders which are characterized by neurobehavioral abnormalities, obesity, congenital abnormalities and so on. However, the prenatal phenotypes of 16p11.2 copy number variations (CNVs) are still not well described till now. This study aimed to provide an elaborate summary of intrauterine phenotypic features for such genomic disorders. Methods: Twenty prenatal amniotic fluid samples diagnosed with 16p11.2 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed in parallel. The pregnancy outcomes and health conditions after birth for all cases were followed up. Meanwhile, we made a pooled analysis on the prenatal phenotypes for the published cases carrying 16p11.2 CNVs. Results: 20 fetuses (20/20884, 0.10%) with 16p11.2 CNVs were identified: five 16p11.2 BP2-BP3 deletion, ten 16p11.2 BP4-BP5 deletion and five 16p11.2 BP4-BP5 duplication. Abnormal ultrasound findings were recorded in ten participants with 16p11.2 deletions.Various degrees of intrauterine phenotypic features, ranging from normal to abnormal, were observed. No ultrasound abnormalities were observed for all 16p11.2 duplication cases during the pregnancy period. For 16p11.2 deletions, eleven cases terminated their pregnancies. For 16p11.2 duplications, four cases gave birth to healthy neonates except one was lost to follow up. Conclusions: Diverse prenatal phenotypes were presented in 16p11.2 CNVs, ranging from normal to abnormal. For 16p11.2 BP4-BP5 deletion, the most common structural and non-structural abnormalities were the abnormality of the vertebral column or rib and thickened nuchal translucency, respectively. 16p11.2 BP2-BP3 deletion might be closely associated with fetal growth restriction and single umbilical artery. No representative ultrasound findings for 16p11.2 duplication were observed till now. Considering the variable expressivity and incomplete penetrance of 16p11.2 CNVs, long term follow up after birth should be carried out for these cases. We identified 20 fetuses carrying the 16p11.2 microdeletions and microduplications using chromosomal microarray analysis. And diverse prenatal phenotypes and the critical genes involved in the deleted/duplicated regions were described in this study.
2024-04-29 | GSE265911 | GEO
Project description:Background - Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human iPSC-derived neurons (iNs) has emerged as a promising strategy. Copy number variations (CNV) confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing risk 14.5 fold. Methods - To dissect the contribution of excitatory (iENs) versus GABAergic (iGNs) neurons to SCZ pathophysiology, we induced iNs from CRISPR-Cas9 engineered isogenic and SCZ patient-derived iPSCs, and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. Results - In iEN/iGN cocultures, we found reduced neuronal network firing rate and synchrony at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for excitatory neurons. Transcriptomic analysis of isogenic 16p11.2 duplication (DUP) iENs revealed pathway dysregulation related to neuroarchitecture and calcium ion binding. Consistent with this, isogenic DUP iENs showed reduced dendrite length and calcium imaging revealed deficits in calcium handling. Analysis of iENs from 16p11.2 duplication-carrying SCZ patients (SCZ) revealed overlapping deficits in network synchrony, dendrite arborization and calcium handling. Conclusions - Our results indicate 16p11.2 duplication-dependent alterations to SCZ neurodevelopment. Calcium ion binding was the only altered transcriptomic gene set shared between isogenic and patient-derived iENs, suggesting a central role of calcium signaling in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers and supports network synchrony and calcium handling as outcomes directly linked to this genetic mutation.
2022-10-13 | GSE215183 | GEO
Project description:The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2. The genome-wide transcript perturbations correlated with clinical endophenotypes of the CNV and were enriched for genes associated with ASD. We uncovered a significant correlation between copy number changes and expression levels of genes mutated in ciliopathies.
2015-05-10 | GSE57802 | GEO
Project description:Recurrent Copy Number Variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a ‘behavior trap’ phenotype—a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. Our findings indicate that 16p11.2 CNVs cause both brain and behavioral anomalies, providing new insight into human neurodevelopmental disorders.
2011-10-03 | GSE32012 | GEO
Project description:The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.
2020-07-27 | GSE155131 | GEO
Project description:Prenatal phenotypes and pregnancy outcomes of fetuses with 16p11.2 microdeletion/microduplication
| PRJNA1104671 | ENA
Project description:As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes.
2017-06-23 | GSE100387 | GEO
Project description:Using mouse genetic studies and systematic assessments of brain neuroanatomical phenotypes, we set out to identify which of the 30 genes causes brain defects at the autism-associated 16p11.2 locus. We show that multiple genes mapping to this region interact to regulate brain anatomy, with female mice exhibiting far fewer brain neuroanatomical phenotypes. In male mice, among the 13 genes associated with neuroanatomical defects (Mvp, Ppp4c, Zg16, Taok2, Slx1b, Maz, Fam57b, Bola2, Tbx6, Qprt, Spn, Hirip3 and Doc2a), Mvp is the top driver implicated in phenotypes pertaining to brain, cortex, hippocampus, ventricles and corpus callosum sizes. The major vault protein (MVP), the main component of the vault organelle, is a conserved protein found in eukaryotic cells, yet its function is not understood. Here, we find MVP expression highly specific to the limbic system and show that Mvp regulates neuronal morphology, postnatally and specifically in males. We also recapitulate a previously reported genetic interaction and show that Mvp+/-;Mapk3+/- mice exhibit behavioral deficits, notably decreased anxiety-like traits detected in the elevated plus maze and open field paradigms. Our study highlights multiple gene drivers in neuroanatomical phenotypes, interacting with each other through complex relationships. It also provides the first evidence for the involvement of the major vault protein in the regulation of brain size and neuroanatomy, specifically in male mice.
2023-09-15 | GSE243261 | GEO