RNA sequencing of blood from sex- and age-matched discordant siblings supports immune and transcriptional dysregulation in Autism Spectrum Disorder.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212645 | GEO | 2023/02/05
REPOSITORIES: GEO
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Project description:The goals of this study were to: 1) investigate changes in DNA methylation in lymphoblastoid cell lines (LCL) from individuals with a specific subtype of ASD and their respective non-autistic siblings, 2) relate the differentially methylated genes to ASD-relevant pathways and functions, and 3) explore the potential for class determination (case-control) biomarkers based on methylation signatures.
2021-03-21 | GSE99935 | GEO
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental condition with onset in early childhood, still diagnosed only through clinical observation due to the lack of laboratory biomarkers. Early detection strategies would be especially useful in screening high-risk newborn siblings of children already diagnosed with ASD. We performed RNA sequencing on peripheral blood, comparing 27 pairs of ASD children vs their sex- and age-matched unaffected siblings. Differential gene expression profiling, performed applying an unpaired model found two immune genes, EGR1 and IGKV3D-15, significantly upregulated in ASD patients (both p adj = 0.037). Weighted gene correlation network analysis identified 18 co-expressed modules. One of these modules was downregulated among autistic individuals (p = 0.035) and a ROC curve using its eigengene values yielded an AUC of 0.62. Genes in this module are primarily involved in transcriptional control and its hub gene, RACK1, encodes for a signaling protein critical for neurodevelopment and innate immunity, whose expression is influenced by various hormones and known "endocrine disruptors". These results indicate that transcriptomic biomarkers can contribute to the sensitivity of an intra-familial multimarker panel for ASD and provide further evidence that neurodevelopment, innate immunity and transcriptional regulation are key to ASD pathogenesis.
| S-EPMC9842630 | biostudies-literature
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:Here we report metagenomic sequencing data in gut microbiota of autism spectrum disorders (ASD) compared with healthy volunteers (30 for ASD children and 30 for healthy controls, respectively). The genes changed in autistic subjects involved 1,312,364 analytes that compare to 1,335,835 analytes in healthy controls. The number of taxa in autistic subjects were significantly increased as compared to the healthy controls based on the phylum and genus level (P = 0.001). However, the number of species were significantly decreased in autistic subjects (P = 0.001).
2020-09-30 | GSE113540 | GEO
Project description:Autism spectrum disorder (ASD) is an early onset neurodevelopmental disorder, which is characterized by disturbances of brain function and behavioral deficits in core areas of impaired reciprocal socialization, impairment in communication skills, and repetitive or restrictive interests and behaviors. ASD is known to have a significant genetic risk, but the underlying genetic variation can be attributed to hundreds of genes. The molecular and pathophysiologic basis of ASD remains elusive because of its genetic heterogeneity and complexity, its high comorbidity with other diseases, and the paucity of brain tissue for study. The invasive nature of collecting primary neuronal tissue from patients might be circumvented through reprogramming peripheral cells to induced pluripotent stem cells (iPSCs), which are able to generate live neurons carrying the genetic variants of disease. This breakthrough allows us to access the cellular and molecular phenotypes of patients with âintrinsic autismâ, that is patients without known genetic disorders or identifiable syndromes or malformations. To do this, we studied a relatively homogeneous patient population of boys with intrinsic autism by excluding patients with known genetic disease or recognizable phenotypes or syndromes, as well as those with profound mental retardation or primary seizure disorders. We generated iPSCs from patients with intrinsic autism, their unaffected male siblings and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons. The expression profile for autistic and their unaffected siblings' iPSC-derived neurons were compared. A distinct expression profile was found between autism and sib control. The significantly differentially expressed genes (> 2-fold, FDR < 0.05) in autistic iPSC-derived neurons were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions (FDR < 0.05), and were significantly enriched for genes previously associated with ASD (p < 0.05). Our findings suggest approaches such as iPSC-derived neurons will be an important method to obtain tissue for study that appropriately recapitulates the complex dynamics of an autistic neural cell. We generated induced pluripotent stem cells (iPSCs) from male patients with intrinsic autism, their unaffected male siblings, and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons following 80 days of post-mitotic neural differentiation. These samples, including fibroblast, iPSC, iPSC-derived neural progenitors (NPC) and iPSC-derived neurons, were analyzed for the change of gene expression profile by whole genome microarray.
2016-07-01 | E-GEOD-65106 | biostudies-arrayexpress
Project description:Autism spectrum disorder (ASD) manifests as alterations in complex human behaviors including social communication and stereotypies. In addition to genetic risks, the gut microbiome differs between typically-developing (TD) and ASD individuals, though it remains unclear whether the microbiome contributes to symptoms. We transplanted gut microbiota from human donors with ASD and TD controls into germ-free mice, and reveal that colonization with ASD microbiota was sufficient to induce hallmark autistic behaviors. The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes. Microbiome and metabolome profiles of mice harboring human microbiota predict that specific bacterial taxa and their metabolites modulate ASD behaviors. Indeed, treatment of an ASD mouse model with candidate microbial metabolites improves behavioral abnormalities and affects neuronal excitability in the brain. We propose that the gut microbiome modulates behaviors in mice via production of neuroactive metabolites, suggesting that gut-brain connections contribute to the pathophysiology of ASD.
2019-07-04 | MTBLS726 | MetaboLights
Project description:Autism spectrum disorder (ASD) is an early onset neurodevelopmental disorder, which is characterized by disturbances of brain function and behavioral deficits in core areas of impaired reciprocal socialization, impairment in communication skills, and repetitive or restrictive interests and behaviors. ASD is known to have a significant genetic risk, but the underlying genetic variation can be attributed to hundreds of genes. The molecular and pathophysiologic basis of ASD remains elusive because of its genetic heterogeneity and complexity, its high comorbidity with other diseases, and the paucity of brain tissue for study. The invasive nature of collecting primary neuronal tissue from patients might be circumvented through reprogramming peripheral cells to induced pluripotent stem cells (iPSCs), which are able to generate live neurons carrying the genetic variants of disease. This breakthrough allows us to access the cellular and molecular phenotypes of patients with ‘intrinsic autism’, that is patients without known genetic disorders or identifiable syndromes or malformations. To do this, we studied a relatively homogeneous patient population of boys with intrinsic autism by excluding patients with known genetic disease or recognizable phenotypes or syndromes, as well as those with profound mental retardation or primary seizure disorders. We generated iPSCs from patients with intrinsic autism, their unaffected male siblings and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons. The expression profile for autistic and their unaffected siblings' iPSC-derived neurons were compared. A distinct expression profile was found between autism and sib control. The significantly differentially expressed genes (> 2-fold, FDR < 0.05) in autistic iPSC-derived neurons were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions (FDR < 0.05), and were significantly enriched for genes previously associated with ASD (p < 0.05). Our findings suggest approaches such as iPSC-derived neurons will be an important method to obtain tissue for study that appropriately recapitulates the complex dynamics of an autistic neural cell.
2016-07-01 | GSE65106 | GEO
Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by abnormalities in reciprocal social interactions and language development and/or usage, and by restricted interests and repetitive behaviors. Differential gene expression of neurologically relevant genes in lymphoblastoid cell lines from monozygotic twins discordant in diagnosis or severity of autism suggested that epigenetic factors such as DNA methylation or microRNAs (miRNAs) may be involved in ASD. The goal of this study was to reveal dysregulation in miRNA levels that are inversely correlated with altered levels of target genes that, in turn, may be associated with the underlying pathophysiology of ASD, and to provide a better understanding of the role of miRNAs as a post-transcriptional gene regulatory mechanism associated with ASD. Lymphoblastoid cell lines (LCLs) derived from peripheral lymphocytes of 14 male subjects were obtained from the Autism Genetic Resource Exchange (AGRE, Los Angeles, CA). The subjects included three pairs of monozygotic twins discordant for diagnosis of autism, a normal sibling for 2 of the twin pairs, two pairs of autistic and unaffected siblings, and a pair of normal monozygotic twins. Global miRNA expression profiling of these LCLs was performed using high-throughput miRNA microarray analysis. A reference design was used for microarray hybridization in this study. The sample miRNAs were coupled with Cy3, whereas the common reference miRNA was coupled with Cy5, and two-colored miRNA microarray analyses were carried out by cohybridizing an equal amount of both miRNA samples onto one slide. Selected differentially expressed miRNAs were confirmed by quantitative RT-PCR, and the putative target genes of two of the confirmed miRNAs were validated by knockdown and overexpression of the respective miRNAs.
2010-04-09 | E-GEOD-21086 | biostudies-arrayexpress
Project description:We recently identified heterozygous deletions of the gene TSHZ3, which encodes a Zn-finger transcription factor, in patients with a syndrome including autistic features and provided evidence in mice for a link between Tshz3 haploinsufficiency, defects in cortical projection neurons (CPNs) and autism spectrum disorder (ASD)-like abnormalities. To get more insight into when and where TSHZ3 is required for the proper development of the brain, we generated and characterized a novel mouse model of conditional Tshz3 deletion in projection neurons from postnatal day 2-3 onward. These mice exhibit altered striatal expression of genes encoding for synaptic components, electrophysiological and synaptic changes in striatal cholinergic interneurons, , as well as ASD-relevant behavioral deficits. These data, by revealing a crucial postnatal role of TSHZ3 in the development and function of the corticostriatal circuitry that might be determinant for ASD pathogenesis, offer a novel ASD model and further open the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.
2020-09-09 | GSE157658 | GEO
Project description:We recently identified heterozygous deletions of the gene TSHZ3, which encodes a Zn-finger transcription factor, in patients with a syndrome including autistic features and provided evidence in mice for a link between Tshz3 haploinsufficiency, defects in cortical projection neurons (CPNs) and autism spectrum disorder (ASD)-like abnormalities. To get more insight into when and where TSHZ3 is required for the proper development of the brain, we generated and characterized a novel mouse model of conditional Tshz3 deletion in projection neurons from postnatal day 2-3 onward. These mice exhibit altered cortical expression of genes encoding for synaptic components, electrophysiological and synaptic changes in layer 5 CPNs, impaired corticostriatal glutamate transmission and plasticity, as well as strong ASD-relevant behavioral deficits. These data, by revealing a crucial postnatal role of TSHZ3 in the development and function of the corticostriatal circuitry that might be determinant for ASD pathogenesis, offer a novel ASD model and further open the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.
2021-09-10 | GSE119791 | GEO