High-throughput Functional Analysis of Autism Genes in Zebrafish Identifies Convergence in Dopaminergic and Neuroimmune Pathways
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE205578 | GEO | 2023/03/17
REPOSITORIES: GEO
Similar Datasets
Project description:High-throughput Functional Analysis of Autism Genes in Zebrafish Identifies Convergence in Dopaminergic and Neuroimmune Pathways
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Project description:Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.
| S-EPMC10277173 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a complex set of neurodevelopmental diseases. However, the etiology and pathogenesis of ASD is largely unknown. An integrated proteomics and metabolomics approach was performed on urine sampled from diagnosed ASD children and typical children. All urine protein samples (n= 160) were subjected to data-independent acquisition proteomic analysis and 60 urine samples underwent liquid chromatography-mass spectrometry based on metabolomic analysis. So, this study presents an overview of the molecular mechanism of ASD and offers some potential targets for further early screening.
2022-02-11 | PXD031652 |
Project description:Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein function altering variants in many genes have been shown to contribute to ASD risk; however, understanding the biological convergence across so many genes has been difficult and genetic studies depending on presence of deleterious variation may be limited in implicating highly intolerant genes with shorter coding sequences. Here, we demonstrate that coexpression patterns from human post-mortem brain samples (N = 993) are significantly correlated with the transcriptional consequences of CRISPR perturbations (gene editing, interference and activation) in human neurons (N = 17). Across 71 ASD risk genes, there is significant tissue-specific transcriptional convergence that implicates synaptic pathways. Tissue specific convergence of risk genes is a generalizable phenomenon, shown additionally in schizophrenia (brain) and atrial fibrillation (heart). The degree of this convergence in ASD is significantly correlated with the level of association to ASD from sequencing studies (rho = -0.32, P = 3.03 ×10−65) as well as differential expression in post-mortem ASD brains (rho = -0.23, P = 2.39×10−43). After removing all genes statistically associated with ASD, the remaining positively convergent genes showed intolerance to functional mutations, had shorter coding lengths than the ASD genes and were enriched for genes with clinical reports of potential pathogenic contribution to ASD. These results indicate that leveraging convergent coexpression can identify potentially novel risk genes that are unlikely to be discovered by sequencing studies. Overall, this work provides a simple approach to functionally proxy CRISPR perturbation, demonstrates significant context-specific transcriptional convergence among known risk genes of multiple diseases, and proposes novel ASD risk gene candidates.
2023-01-10 | GSE222259 | GEO
Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.
2010-05-17 | E-GEOD-15402 | biostudies-arrayexpress
Project description:Individualized outcome prediction classifiers were successfully constructed through expression profiling of 91 up-regulated and 67 down-regulated miRNAs in 5 autism spectrum disorder (ASD) cases and 5 controls. In the study presented here, a well-defined cohort of 5 autism spectrum disorder cases and 5 controls was used to acquire expression profiles of 91 up-regulated and 67 down-regulated miRNAs, leading to the first global miRNA expression profile of ASD in China.
2015-04-17 | E-GEOD-67979 | biostudies-arrayexpress
Project description:Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). ChIP-seq was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000bp upstream of transcription start site, was highly predictive of brain expressed genes. This signature was observed at 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After eight days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.
2023-12-04 | GSE248876 | GEO
Project description:Autism spectrum disorder (ASD) is a common, highly heritable neuro-developmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an etiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1/FOX1, and a module enriched for immune genes and glial markers. Using high-throughput RNA-sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in ASD brain. Moreover, using a published autism GWAS dataset, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic etiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. Total RNA was extracted from approximately 100mg of postmortem brain tissue representing Cerebellum (C), Frontal cortex (F), and Temporal cortex (T), from autistic and control individuals.
2011-05-01 | E-GEOD-28521 | biostudies-arrayexpress
Project description:Using DNA microarray as a global approach to understanding the molecular basis of autism, we examined gene expression profiling in peripheral blood from 21 young adults with autism spectrum disorder (ASD) and healthy mothers having children with ASD, between whom there was no blood relationship. Several genes which were significantly changed in the ASD group comparing with their age- and gender-matched healthy subjects were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, mothers having children with ASD possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and healthy mothers having children with ASD. Total RNA was prepared from venous blood which was taken from each subject. Gene expression profiling of venous blood from subjects with ASD (21), the healthy women who had children with ASD (21) and their age- and gender-matched healthy subjects (42) were obtained using a whole human genome oligonucleotide microarray (Agilent 44K Human whole genome array G4112F, GPL6480) to measure gene expression in these samples according to the manufacture’s protocol. The one GSM sample of microarray analysis was made by individual subject. Differentially expressed genes were determined across all rationed expression values for age- and gender-matched pairs (ASD vs. control, asdMO vs. ctrlMO) using Genespling analysis.
2011-01-13 | E-GEOD-26415 | biostudies-arrayexpress
Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males.
2009-12-22 | GSE15402 | GEO