A Single-Cell Atlas of DNA Methylation in Autism Spectrum Disorder Reveals Distinct Regulatory and Aging Signatures
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE298243 | GEO | 2025/06/17
REPOSITORIES: GEO
Similar Datasets
Project description:Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (>200 ASD-risk genes), no single gene mutation accounts for >1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. To investigate the epigenome in patients with ASD, genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450K array in blood from individuals with ASD of heterogeneous, undefined etiology (n=52) and individuals with 16p11.2 deletions (16p11.2del, n=9) or pathogenic variants in the chromatin modifier CHD8 (CHD8+/-, n=7), two of the most common genomic variants conferring increased risk for ASD. DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8+/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8+/- individuals from both heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n=9) and CHD8 (n=9) variants as pathogenic or benign. Our findings that DNAm alterations in each signature targets unique genes in biological pathways relevant to neural development support their functional relevance. Furthermore, genes identified in our CHD8+/- DNAm signature in blood overlapped differentially expressed genes in CHD8+/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. Our study constitutes a novel approach for ASD molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.
2019-09-01 | GSE113967 | GEO
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and repetitive behaviors. MicroRNAs (miRNAs) have been recently recognized as potential biomarkers of ASD as they are dysregulated in various tissues of individuals with ASD. However, it remains unclear whether miRNA expression is altered in individuals with high-functioning ASD. Here, we investigated the miRNA expression profile in peripheral blood from adults with high-functioning ASD, and age and gender-matched healthy controls. Our findings may provide insights regarding the molecular clues for recognizing high-functioning ASD.
2020-05-03 | GSE89596 | 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:Autism spectrum disorder (ASD) diagnosis is increasing, with 1/88 children believed to be affected by the disorder, with a most recent survey suggesting numbers as high as 1/50. Treatment and understanding of ASD causes is a pressing health concern. ASD protein biomarkers may provide clues about ASD cause. Protein biomarkers for ASDs could be used for ASD diagnosis, subtyping, treatment monitoring and identifying therapeutic targets. Here we analyzed the sera from 7 children with ASD and 7 matched controls using Tricine gel electrophoresis (Tricine-PAGE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Overall, we found increased levels of apolipoproteins (Apos) ApoA1 and ApoA4, involved in cholesterol metabolism and of serum paraoxanase/arylesterase 1 (PON1), involved in preventing oxidative damage, in the sera of children with ASD, compared with their matched controls. All three proteins are predicted to interact with each other and are parts of High Density Lipoproteins (HDLs). Further studies are needed to validate these findings in larger subject numbers.
2022-02-22 | PXD000679 | Pride
Project description:Autism spectrum disorder (ASD) is a complex heterogeneous developmental disease with a significant genetic background that is frequently caused by rare copy number variants (CNV). The aim of the study was to identify new candidate genes for ASD in the studied cohort of ASD-diagnosed patients. We used chromosomal microarray analysis (CMA) - a Cytoscan HD (Affymetrix, Santa Clara, CA, USA) to detect CNV in 87 ASD patients and their relatives and evaluated their clinical significance. Pathogenic and likely pathogenic mutations were identified by CMA in 8 and 9 ASD patients, respectively. CMA revealed 89 rare CNV: 8 pathogenic, 12 designated VOUS - likely pathogenic, 12 VOUS - uncertain, and 57 VOUS - likely benign or benign. CNV (pathogenic/VOUS-likely pathogenic/VOUS - uncertain) overlapping the same gene in more than one patient were observed in DOCK8 gene and PARK2 gene. This work presents new evidence about the possible roles of PARK2 and DOCK8 in the etiology of ASD, and suggests CTNNA2 as a candidate gene for ASD risk.
2018-05-25 | GSE114870 | GEO
Project description:Chromosomal abnormalities have been identified in some individuals with Autism Spectrum Disorder (ASD), but their full etiologic role is unknown. Submicroscopic copy number variation (CNV) represents a considerable source of genetic variation in the human genome that contributes to phenotypic differences and disease susceptibility. To explore the contribution CNV imbalances in ASD, we genotyped unrelated ASD index cases using the Affymetrix GeneChip® 500K single nucleotide polymorphism (SNP) mapping array. Keywords: Whole Genome Mapping SNP Genotyping Array
2007-12-20 | GSE9222 | GEO
Project description:To assess the clinical impact of splice-altering noncoding mutations in autism spectrum disorder (ASD), we used a deep learning framework (SpliceAI) to predict the splice-altering potential of de novo mutations in 3,953 individuals with ASD from the Simons Simplex Collection. To validate these predictions, we selected 36 individuals that harbored predicted de-novo cryptic splice mutations; each individual represented the only case of autism within their immediate family. We obtained peripheral blood-derived lymphoblastoid cell lines (LCLs) and performed high-depth mRNA sequencing (approximately 350 million 150 bp single-end reads per sample). We used OLego to align the reads against a reference created from hg19 by substituting de novo variants of each individual with the corresponding alternate allele.
2018-11-25 | E-MTAB-7351 | biostudies-arrayexpress
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease with complex heterogeneity and aberrations in multiple levels of neurobiology. Recently, our understanding of the molecular abnormalities in ASD has been greatly expanded through transcriptomic analyses of postmortem brains. However, a crucial molecular pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled the global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of ASD cortices and cerebella. Strikingly, we observed a global bias of hypoediting in ASD brains, common to different brain regions and involving many genes with critical neurological function. The large-scale RNA editing changes allowed us to reveal novel insights of RNA editing regulation. Through genome-wide protein-RNA binding analyses and detailed molecular assays, we show that the Fragile X proteins, FMRP and FXR1P, interact with ADAR protens and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA editing alterations between ASD and Fragile X syndrome, thus establishing RNA editing as a novel molecular link underlying these two highly related diseases. Our findings support a role for RNA editing dysregulation in ASD pathophysiology and highlight novel mechanisms for RNA editing regulation.
2018-12-14 | GSE117776 | GEO
Project description:To examine how activation of different toll-like receptors (TLR) impacts gene expression in Autism Spectrum Disorder (ASD), we cultured peripheral blood monocytes from children with ASD, Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) or Asperger and typically developing children and treated them with either lipoteichoic acid (LTA) or lipopolysaccharide (LPS) to activate LTR2 or 4 respectively. Following 24 hours of stimulation, we then performed RNA sequencing to profile mRNA responses between non-treated (NT), LTA and LPS treated samples for each diagnosis (control or ASD).
2021-12-17 | GSE140702 | GEO
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