scholarly journals LINE-1 and Alu methylation Signatures in Autism Spectrum Disorder and Their Function in The Regulation of Autism-Related Genes

2021 ◽  
Author(s):  
Thanit Saeliw ◽  
Tiravut Permpoon ◽  
Nutta Iadsee ◽  
Tewin Tencomnao ◽  
Tewarit Sarachana ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Post Mortem ◽  
Global Methylation ◽  
Post Mortem Brain ◽  
Dna Methylation Profiling ◽  
Methylation Profiling

Abstract BackgroundLong interspersed nucleotide element-1 (LINE-1) and Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability. Several studies have focused on DNA methylation profiling of gene regions, but the locus-specific methylation of LINE-1 and Alu elements has not been identified in autism spectrum disorder (ASD).MethodsHere, DNA methylation age was predicted using Horvath’s method. We interrogated locus- and family-specific methylation profiles of LINE-1 and Alu elements (22,352 loci) in ASD blood using publicly-available Illumina Infinium 450K methylation datasets from heterogeneous ASD (n = 52), ASD with 16p11.2 del (n = 7), and ASD with Chromodomain Helicase DNA-binding 8 (CHD8) variants (n = 15). The differentially methylated positions of LINE-1 and Alu elements corresponding to genes were combined with transcriptome data from multiple ASD studies. ROC curve was conducted to examine the specificity of target loci.ResultsEpigenetic age acceleration was significantly decelerated in ASD children over the age of 11 years. DNA methylation profiling revealed LINE-1 and Alu methylation signatures in each ASD risk loci by which global methylation were notably hypomethylated exclusively in ASD with CHD8 variants. When LINE-1 and Alu elements were clustered into subfamilies, we found methylation changes in a family-specific manner in L1P, L1H, HAL, AluJ, and AluS families in the heterogeneous ASD and ASD with CHD8 variants. Our results showed that LINE-1 and Alu methylation within target genes is inversely related to the expression level in each ASD variant. Moreover, LINE-1 and Alu methylation signatures can be used to predict ASD individuals from non-ASD.LimitationsIntegration of methylome and transcriptome datasets was performed from different ASD cohorts. The small sample size of the validation cohort used post-mortem brain tissues and necessitates future validation in a larger cohort.ConclusionsThe DNA methylation signatures of the LINE-1 and Alu elements in ASD, as well as their functional impact on ASD-related genes, have been studied. These findings are considered for further research into DNA methylation profiles and the expression of the LINE-1 and Alu elements in post-mortem brain tissue, which has been linked to ASD pathogenesis.

scholarly journals Peripheral blood DNA methylation and autism spectrum disorder

2018 ◽  
Author(s):  
Shan V. Andrews ◽  
Brooke Sheppard ◽  
Gayle C. Windham ◽  
Laura A. Schieve ◽  
Diana E. Schendel ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Sample Size ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Case Control ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Blood Samples ◽  
Cpg Sites

AbstractBackgroundSeveral reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size, and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies.MethodsDNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample.FindingsIn this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12×10−7. Seven CpGs showed differences at p < 1×10−5 and 48 at 1×10−4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpGs hits, which was consistent across EWAS and meQTL discovery p-value thresholds.ConclusionsWe report the largest case-control EWAS study of ASD to date. No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the 7 sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD.

scholarly journals 2288 Neural correlates of face processing in autism spectrum disorder: A quantitative meta-analysis of current literature and future directions

2018 ◽  
Vol 2 (S1) ◽  
pp. 21-22
Author(s):  
Carla J. Ammons ◽  
Mary-Elizabeth Winslett ◽  
Rajesh K. Kana
Keyword(s):  
Autism Spectrum Disorder ◽  
Face Processing ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Future Research ◽  
Healthy Controls ◽  
Specific Level

OBJECTIVES/SPECIFIC AIMS: Autism spectrum disorder (ASD) affects 1 in 68 people and includes restricted, repetitive behavior, and social communication deficits. Aspects of face processing (i.e., identity, emotion perception) are impaired in some with ASD. Neuroimaging studies have shown aberrant patterns of brain activation and connectivity of face processing regions. However, small sample sizes and inconsistent results have hindered clinical utility of these findings. The study aims to establish consistent patterns of brain responses to faces in ASD and provide directions for future research. METHODS/STUDY POPULATION: Neuroimaging studies were identified through a multi-database search according to PRISMA guidelines. In total, 23 studies were retained for a sample size of 383 healthy controls and 345 ASD. Peak coordinates were extracted for activation likelihood estimation (ALE) in GingerALE v2.3.6. Follow-up ALE analyses investigated directed Versus undirected gaze, static Versus dynamic, emotional Versus neutral, and familiar Versus unfamiliar faces. RESULTS/ANTICIPATED RESULTS: Faces produced bilateral activation of the fusiform gyrus (FG) in healthy controls (−42 −52 −20; 22 −74 −12, p<0.05, FDR) and left FG activation in ASD (−42 −54 −16, p<0.05, FDR). Activation in both groups was lateral to the mid-fusiform sulcus. Follow-up results pending. DISCUSSION/SIGNIFICANCE OF IMPACT: Reduced right FG activation to faces may inform biomarker or response to intervention studies. Mid-fusiform sulcus proved a reliable predictor of functional divides should be investigated on a subject-specific level.

scholarly journals DNA Methylation and Susceptibility to Autism Spectrum Disorder

2019 ◽  
Vol 70 (1) ◽  
pp. 151-166 ◽  
Author(s):  
Martine W. Tremblay ◽  
Yong-hui Jiang
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Causative Factor ◽  
Autism Spectrum ◽  
Postnatal Period ◽  
Spectrum Disorder ◽  
Regulation Of Transcription ◽  
Peak Time ◽  
Genome Wide ◽  
Technical Advances

The prevalence of autism spectrum disorder (ASD) has been increasing steadily over the last 20 years; however, the molecular basis for the majority of ASD cases remains unknown. Recent advances in next-generation sequencing and detection of DNA modifications have made methylation-dependent regulation of transcription an attractive hypothesis for being a causative factor in ASD etiology. Evidence for abnormal DNA methylation in ASD can be seen on multiple levels, from genetic mutations in epigenetic machinery to loci-specific and genome-wide changes in DNA methylation. Epimutations in DNA methylation can be acquired throughout life, as global DNA methylation reprogramming is dynamic during embryonic development and the early postnatal period that corresponds to the peak time of synaptogenesis. However, technical advances and causative evidence still need to be established before abnormal DNA methylation and ASD can be confidently associated.

scholarly journals The Effectiveness of Equine-Based Therapy in the Treatment of Social and Behavioural Aspects of Children with Autism Spectrum Disorder: A Systematic Review

2016 ◽  
Author(s):  
Courtney Wiese ◽  
Rebecca Simpson ◽  
Saravana Kumar
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Interactions ◽  
Outcome Measures ◽  
Methodological Quality ◽  
Small Sample Size ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Children With Asd ◽  
Behavioural Aspects

Introduction: Individuals with Autism spectrum disorder (ASD) present with impairments in social interactions, communication, restricted, repetitive and stereotyped patterns of behaviour, interests or activities. Equine-based therapy is used as a treatment with children with disabilities. There have been no systematic reviews conducted on the effectiveness of equine-based therapy in children with ASD. Purpose: To examine the effectiveness of equine-based therapy on behavioural and social interactions in the treatment of children with ASD. Methods: A systematic search of Cochrane, OT Seeker, MEDLINE, Embase, CINAHL, PsychINFO, Informit health databases and Proquest central were conducted. Studies of participants, aged 4-16 years, with professional diagnosed ASDs were included if they utilised outcome measures assessing behaviours and social interactions through questionnaire or observation. A critical appraisal, using the McMaster Critical Review Form for Quantitative Studies, was performed to assess methodological quality. NHMRC body of evidence framework was used to provide the study with an overall grade of recommendation in assessing quality of evidence. Results: Eight studies of varying research designs and methodological quality met the inclusion criteria. The participants in these studies were aged between 4-16 years of age. The duration of the inventions ranged from 6-12 weeks, and each study used varied measures of outcome. Overall, studies showed some improvements in behaviours and social interactions following an equine-based therapy intervention. Conclusions: Few studies have investigated the effect of equine therapy on behaviour and social interactions of children with ASD. The current body of evidence is constrained by small sample size, lack of comparator, crude sampling methods, and the lack of standardised outcome measures. Equine-based therapy shows potential as a treatment method for behaviours and social interactions in children with ASD.

scholarly journals DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

2021 ◽  
Author(s):  
Sophia Bam ◽  
Erin Buchanan ◽  
Caitlyn Mahony ◽  
Colleen O’Ryan
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Mitochondrial Dysfunction ◽  
Copy Number ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Peroxisome Proliferator ◽  
Mtdna Copy Number ◽  
Cpg Sites ◽  
Mtdna Deletions

AbstractBackgroundAutism Spectrum Disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including canonical mitochondrial pathways. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the aetiology of ASD. We examined the relationship between DNA methylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), an essential transcriptional regulator of mitochondrial homeostasis, and mitochondrial dysfunction in an ASD cohort of South African children.ResultsUsing targeted Next Generation bisulfite sequencing, we found 12 highly variable CpG sites in PGC-1α that were significantly differentially methylated (p<0.05) between ASD (n = 55) and controls (n = 44). In ASD, eight CpG sites were hypermethylated in the PGC-1α promotor with a putative binding site for CAMP response binding element 1 (CREB1) spanning one of these CpG sites (p = 1 × 10−6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter. There was a positive correlation between methylation at PGC-1α at CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD, but a negative correlation between methylation at PGC-1α at CpG#4 promoter and mtDNA copy number in controls (Spearman’s r = −0.4, n = 42, p = 0.045). While there was no relationship between mtDNA deletions and PGC-1α methylation in ASD, mtDNA deletions correlated negatively with methylation at PGC-1α at CpG#4 (Spearman’s r = −0.4, n = 42, p = 0.032) in controls. Furthermore, levels of urinary organic acids associated with mitochondrial dysfunction correlated significantly (p<0.05) with DNA methylation at PGC-1α CpG#1 and mtDNA copy number in ASD (n= 20) and controls (n= 13) with many of these metabolites involved in altered redox homeostasis and neuroendocrinology.ConclusionsThese data show an association between PGC-1α promoter methylation, elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored link between DNA methylation and mitochondrial dysfunction in ASD.

scholarly journals An epigenetic biomarker for adult high-functioning autism spectrum disorder

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ryo Kimura ◽  
Masatoshi Nakata ◽  
Yasuko Funabiki ◽  
Shiho Suzuki ◽  
Tomonari Awaya ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
High Functioning Autism ◽  
Autism Spectrum ◽  
Machine Learning Algorithms ◽  
Spectrum Disorder ◽  
Methylation Array ◽  
High Functioning ◽  
Epigenetic Biomarkers ◽  
Potential Marker

Abstract Increasing evidence suggests that epigenetic mechanisms play a role in the etiology of autism spectrum disorder (ASD). To date, several studies have attempted to identify epigenetic biomarkers for ASD. However, reliable markers remain to be established and most of these studies have focused on pediatric patients with ASD. In this study, we sought to find an epigenetic DNA methylation biomarker from peripheral blood for adult patients with high-functioning ASD. DNA methylation profiles were analyzed using the Illumina 450 K methylation array. To identify robust candidate markers, we employed two types of machine-learning algorithms for marker selection. We identified a potential marker (cg20793532) for which is the AUC value was 0.79. Notably, cg20793532 was annotated to the PPP2R2C gene, which was hypermethylated and down-regulated in blood from ASD patients compared to that in the controls. Although requiring careful interpretation, this pilot study seems to provide a potential blood biomarker for identifying individuals with high-functioning ASD.

The Feasibility and Acceptability of Delivering Pivotal Response Treatment for Autism Spectrum Disorder via Telehealth: A Pilot Study (Preprint)

2021 ◽  
Author(s):  
Krista Nicole Drapalik ◽  
David Grodberg ◽  
Pamela Ventola
Keyword(s):  
Autism Spectrum Disorder ◽  
Parent Training ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Training Condition ◽  
Stepped Care ◽  
Pivotal Response Treatment ◽  
Clinical Effects ◽  
Children With Asd

BACKGROUND Pivotal Response Treatment (PRT), an evidence-based and parent-delivered intervention, is designed to improve social communication in individuals with autism spectrum disorder (ASD). OBJECTIVE To assess the feasibility, acceptability, and clinical effects of an online model of PRT delivered via MindNest Health that aims to provide self-directed and engaging online modules, real-time coaching and feedback, and accessible stepped-care to large populations of parents seeking resources for their children with ASD. METHODS Male and female children, ages 2-7 years old with single-word to phrase-level speech, were eligible to participate in the study. Families were randomized to the online parent training condition or control condition. The online component of the intervention consisted of eight 20-minute online courses of content describing parent training principles in PRT. Four 1-hour videoconferences were held after course 1, course 3, course 5, and course 8. Parents were given 1-2 weeks to complete each course. Parents completed the Client Expectancies Questionnaire (CCQ) at Week 2 and endpoint, as well as the Behavioral Intervention Rating Scale (BIRS) at endpoint to assess parental expectancies and treatment acceptability and effectiveness. RESULTS 9 of 14 subjects completed the study curriculum in the online parent training condition, and 6 of 12 subjects completed the control condition. A total of 58% subjects completed study curriculum by study closure. Within the online parent training condition, there was a significant increase in mean CCQ Total Scores from 25.38 ± 3.25 at baseline to 27.5 ± 3.74 at endpoint (P = .04), mean CCQ Confidence Scores from 6.0 ± 1.07 at baseline to 6.75 ± 0.89 at endpoint (P = .02), and mean CCQ Other Improvement Scores 5.25 ± 0.89 at baseline to 6.25 ± 1.28 at endpoint (P = .009). Within the control condition, a modest increase in CCQ scores existed (Confidence △M = +.25; Recommend △M = +.25; Total Score △M = +.50), but no significant results were found (Confidence P = .38; Recommend P = .36; Total Score P = .43). Out of the eleven parents that completed the BIRS at endpoint, 83% parents endorsed they slightly agree or agree with over 93% of the Acceptability factor items on the BIRS. CONCLUSIONS The feasibility of this online treatment is endorsed by the high rate of online module completion and attendance to videoconferences within the online parent training group. Acceptability of treatment is supported by strong ratings on the CCQ and significant improvements in scores as well as strong ratings on the BIRS. This study’s small sample size limits the conclusions that can be drawn, however, the PRT MindNest Health platform holds promise to support parents of children with ASD who are unable to access traditional, in-person parent-mediated intervention for their child.

scholarly journals Herbal Medicine Treatment for Children with Autism Spectrum Disorder: A Systematic Review

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Miran Bang ◽  
Sun Haeng Lee ◽  
Seung-Hun Cho ◽  
Sun-Ae Yu ◽  
Kibong Kim ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Herbal Medicine ◽  
Rating Scale ◽  
Small Sample Size ◽  
Herbal Medicines ◽  
Effective Rate ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Qualitative Synthesis

Objective. To summarize and evaluate the efficacy and safety of herbal medicines used for the treatment of autism spectrum disorder (ASD) in children. Methods. Thirteen electronic databases were searched from their inception to November 2016. Randomized controlled trials (RCTs) that assessed the efficacy of herbal medicines alone or in combination with other Traditional Chinese Medicine treatments for ASD in children were included. The Cochrane Risk of Bias Tool was used and other data analyses were performed using RevMan (Version 5.3). Results. Ten RCTs involving 567 patients with ASD were included for qualitative synthesis. In conjunction with conventional therapy, herbal medicines significantly improved the Childhood Autism Rating Scale (CARS) score, but the results of effects on total effective rate (TER) were different between the included studies. The use of herbal medicines with integrative therapy improved the CARS score and TER. In the studies that documented adverse events, no serious events were associated with herbal medicines. Conclusions. The efficacy of herbal medicines for the treatment of ASD appears to be encouraging but was inconclusive owing to low methodological quality, herbal medicine diversity, and small sample size of the examined studies.

scholarly journals MOSAIC EPIGENETIC DYSREGULATION OF ECTODERMAL CELLS IN AUTISM SPECTRUM DISORDER

2014 ◽  
Author(s):  
Esther R. Berko ◽  
Masako Suzuki ◽  
Faygel Beren ◽  
Christophe Lemetre ◽  
Christine M. Alaimo ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Dna Mutations ◽  
Genome Wide ◽  
Methylation Assay ◽  
Increased Risk ◽  
Methylation Patterns ◽  
Encoding Protein

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested an homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

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