RNA-seq of 36 individuals with autism spectrum disorder
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 4000
ORGANISM(S): Homo sapiens
SUBMITTER: Fazel Darbandi Siavash
PROVIDER: E-MTAB-7351 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:<p>It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 617 individual exomes from 209 families deposited in dbGaP. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.</p>
| phs000482 | dbGaP
Project description:For decades, technical and cost hurdles have prevented the systematic investigation of non-coding sequences in complex human diseases, and thus our knowledge about autism spectrum disorders (ASD) has been primarily obtained from analysis of protein-coding sequences. We have combined the analysis of whole genome sequencing with global studies of regulatory sequences of human cortical neurons to reveal the regulatory architecture of ASD. Analysis of de novo mutations from whole genome sequencing of 261 autism families revealed the physical proximity of ASD de novo mutations specifically to the cortical expression quantitative loci (eQTLs) of synaptic genes. We performed ATAC-Seq, ChIP-Seq, RNA-Seq and Hi-C experiments on human cortical neurons, which for the first time provided a paranormal view of the regulatory landscape in these cells. We found that ASD de novo mutations preferentially affect regulatory elements, and the associated genes are shared targets of two ASD syndromic factors, CHD8 and PTEN. Analyzing 15 chromatin states across 127 human tissue/cell types revealed a significant enrichment of ASD de novo mutations in active transcription start sites and the perturbed genes implicated in neuron functions; this distribution enabled us to develop a machine-learning algorithm to assess potential ASD risk for a given individual. Taken together, our study for the first time revealed the regulatory landscape in human neurons, demonstrated the importance of the non-coding genome in ASD and provides a general framework for analyzing regulatory mutations for other complex human diseases.
2022-11-20 | GSE79965 | GEO
Project description:Whole-exome sequencing studies have implicated chromatin modifiers and transcriptional regulators in autism spectrum disorder (ASD) through the identification of de novo loss of function mutations in affected individuals. Many of these genes are co-expressed in mid-fetal human cortex, suggesting ASD risk genes converge in regulatory networks that are perturbed in ASD during neurodevelopment. To elucidate such networks we mapped promoters and enhancers bound by the chromodomain helicase CHD8, which is strongly enriched in ASD-associated de novo loss of function mutations, using ChIP-seq in mid-fetal human brain, human neural stem cells (hNSCs), and embryonic mouse cortex. We find that CHD8 targets are strongly enriched for ASD risk genes that converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in significant dysregulation of ASD risk genes targeted by CHD8, as well as additional genes important for neurodevelopment, including members of the Wnt/M-NM-2-catenin signaling pathway. Integration of CHD8 binding data with genetic and gene co-expression data in ASD risk models provides support for additional ASD risk genes. Together, our results suggest that loss of CHD8 function contributes to ASD through regulatory perturbation of other ASD risk genes during human cortical development. Two biological replicates for each ChIP with appropriate Input control Four biological replicates for each condition in knockdown experiments (Ctrl construct, Chd8 target C, and Chd8 target G)
2015-01-21 | E-GEOD-57369 | biostudies-arrayexpress
Project description:Autism spectrum disorder (ASD) and mental retardation (MR) represent clinically distinct neurodevelopmental disorders with a complex genetic etiology. Using microarrays we identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated ASD and MR patients; DNA sequencing of SHANK2 revealed additional variants including a de novo nonsense mutation and 7 rare inherited changes. Our findings further link common genes between ASD and intellectual disability.
2010-05-01 | GSE20533 | GEO
Project description:<p>It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 617 individual exomes from 209 families deposited in dbGaP. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.</p>
| phs000482.v1.p1 | EGA
Project description:Whole-exome sequencing studies have implicated chromatin modifiers and transcriptional regulators in autism spectrum disorder (ASD) through the identification of de novo loss of function mutations in affected individuals. Many of these genes are co-expressed in mid-fetal human cortex, suggesting ASD risk genes converge in regulatory networks that are perturbed in ASD during neurodevelopment. To elucidate such networks we mapped promoters and enhancers bound by the chromodomain helicase CHD8, which is strongly enriched in ASD-associated de novo loss of function mutations, using ChIP-seq in mid-fetal human brain, human neural stem cells (hNSCs), and embryonic mouse cortex. We find that CHD8 targets are strongly enriched for ASD risk genes that converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in significant dysregulation of ASD risk genes targeted by CHD8, as well as additional genes important for neurodevelopment, including members of the Wnt/β-catenin signaling pathway. Integration of CHD8 binding data with genetic and gene co-expression data in ASD risk models provides support for additional ASD risk genes. Together, our results suggest that loss of CHD8 function contributes to ASD through regulatory perturbation of other ASD risk genes during human cortical development.
2015-01-21 | GSE57369 | GEO
Project description:E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Neurodevelopmental Disorders such as Autism Spectrum Disorder (ASD) and Developmental Delay (DD). This study identifies the impact of the ASD-associated de novo Cul3-mutation on brain anatomy, behavior, molecular, cellular, and circuit-level mechanisms during early neocortical development. We report that Cul3 mutant mice have microcephaly and severe brain structure defects. This mouse model exhibits social and cognitive deficits and hyperactivity behavior. Spatiotemporal transcriptomic and proteomic profiling of Cul3 mouse brain implicates neurogenesis and cytoskeletal defects as key drivers of Cul3 functional effect. We show that Cul3 is critical for neuron growth and development. Cultured cortical neurons from the mutant mice have reduced dendritic length, actin cytosketon defects, reduced network activity, and increased cell death. At the molecular level, we implicate upregulation of small GTPase RhoA, involved in regulation of cytoskeletal dynamics, and neurite outgrowth as one of the pathways impacted by the de novo Cul3 mutations in ASD. Treatment with small molecule RhoA inhibitor Rhosin rescues dendrite length phenotype and implicates RhoA pathway in ASD.
2021-03-16 | GSE144046 | GEO
Project description:Based on a transcriptomic and functional approach, we performed ex-vivo studies on fibroblasts originated from a patient with Intellectual Disability and Autism Spectrum Disorders (ID-ASD) carrying a nonsense de novo mutation in CSDE1. The aim is to decipher the CSDE1-dependent biological pathways involved in the pathophysiology of ID-ASD. We identified the Wnt/β-catenin pathway and cell adhesion as two deregulated cellular pathways deregulated in the ID-ASD patient.
2023-12-09 | GSE162954 | GEO
Project description:Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the 9 ASD genes examined, 7 were misexpressed in the cortices of Tbr1 knockout mice, including 6 with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.
2016-06-17 | GSE71384 | GEO
Project description:<p>Autism spectrum disorder (ASD) is highly heritable with recent sibling recurrence risk estimates of 19% overall and 26% in males. The heritable phenotype of hyperserotonemia, or elevated levels of platelet serotonin (5HT), in ~35% of people with ASD is a well-established biomarker. The efficacy of drugs like risperidone and potent serotonin transporter inhibitors at treating behaviors related to Insistence on Sameness, along with evidence of the contribution of hyperserotonemia to autism susceptibility collectively support the hypothesis that dysfunction in the 5HT system is a significant etiological target for investigation of the genetic component to autism. ASD genetic architecture is complex; common variants of large effect do not contribute substantially to overall ASD risk, but there are clearly common variants with small effects and rare genetic/genomic variation of larger effect among ASD genetic risk factors. The NIH ARRA Autism Sequencing Consortium, including Dr. Sutcliffe and Dr. Cook among others, has initiated exome sequencing studies to identify more of the rare variants contributing to ASD. Data from our group and others reveal numerous rare <i>de novo</i> and inherited sequence mutations, and the number of <i>de novo</i> and other functional mutations that are found to affect molecules encoding 5HT signaling and its regulation further reinforces our hypothesis that regulation of serotonin levels is important in autism genetic susceptibility. Integrin receptor signaling pathways were prominently featured among identified de novo mutations, thus defining a set of interrelated gene networks that control 5HT signaling. We propose to extend our findings to date by conducting exome sequencing on ACE subjects, for whom we also have 5HT biochemical data, to identify rare variants (including CNVs) in 5HT-related gene networks. In total we propose to have exome sequencing completed on 523 samples. The purpose of the proposed research is two-fold: 1) we will conduct more extensive investigations to determine the support for the hypothesis that genetic variation at genes regulating platelet serotonin levels affect susceptibility to ASD and 2) we will combine the exome sequence data from these studies with sequence data for autism being accumulated in a variety of other research projects to further the goal of identifying and characterizing the genetic component to ASD.</p>
| phs000712 | dbGaP