scholarly journals Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder

2016 ◽  
Author(s):  
Shan V. Andrews ◽  
Shannon E. Ellis ◽  
Kelly M. Bakulski ◽  
Brooke Sheppard ◽  
Lisa A. Croen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Joint Analysis ◽  
Tissue Integration ◽  
Insight Into

ABSTRACTIntegration of emerging epigenetic information with Autism Spectrum Disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. We use genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists) and additionally use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; p < 0.001) and peripheral blood meQTLs (OR = 1.58; p < 0.001). The CpG targets of ASD meQTLs across cord, blood, and brain tissues are enriched for immune-related pathways, consistent with other expression and DNAm results in ASD, and reveal pathways not implicated by genetic findings. This joint analysis of genotype and DNAm demonstrates the potential of both brain and blood-based DNAm for insights into ASD and psychiatric phenotypes more broadly.

scholarly journals Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

2019 ◽  
Author(s):  
Charles E. Mordaunt ◽  
Julia M. Jianu ◽  
Ben Laufer ◽  
Yihui Zhu ◽  
Keith W. Dunaway ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Cord Blood ◽  
Neurodevelopmental Disorder ◽  
Familial Risk ◽  
Fetal Brain ◽  
Cell Types ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Blood Samples ◽  
Genome Bisulfite Sequencing

AbstractBackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. Since the neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development, we performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth.ResultsWe identified differentially-methylated regions (DMRs) stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development.ConclusionsAt birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD, and provides novel insights for early diagnosis and therapy.

scholarly journals Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Shan V. Andrews ◽  
Shannon E. Ellis ◽  
Kelly M. Bakulski ◽  
Brooke Sheppard ◽  
Lisa A. Croen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Tissue Integration ◽  
Insight Into

scholarly journals Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Charles E. Mordaunt ◽  
Julia M. Jianu ◽  
Benjamin I. Laufer ◽  
Yihui Zhu ◽  
Hyeyeon Hwang ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Cord Blood ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Chromosome Location ◽  
Blood Samples ◽  
Chromatin States ◽  
Males And Females

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes. Methods We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females. Results We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development. Conclusions At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.

scholarly journals Fleeting: a Novel Ultrasonic Vocalization in Mice That Allows to Define Altered Developmental Milestones in Autism Spectrum Disorder

2022 ◽  
Author(s):  
Helena Ferreira ◽  
Sofia Santos ◽  
João Martins ◽  
Miguel Castelo-Branco ◽  
Joana Gonçalves
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Ultrasonic Vocalizations ◽  
Spectrum Disorder ◽  
Gradual Loss ◽  
Major Mode ◽  
Age Dependent ◽  
Communication Impairments ◽  
Insight Into ◽  
Time Point

Abstract A major mode of rodent communication occurs through ultrasonic vocalizations (USVs), which are influenced by environmental factors, mouse strain or genetic background and, importantly, by developmental stage. However, few studies have looked into the age-dependent evolution of spectral features of mouse USVs. Here, we report the existence of a novel vocalization, previously unreported, which we named “Fleeting” consisting of two acoustic elements produced with a narrow silent temporal interval between them. Strikingly, this vocalization pattern was extinguished after the second postnatal week, and this temporal pattern was associated with increased emission of Complex vocalizations, by gradual loss of the inter-element interval, suggesting a maturation process occurring at this time point. Importantly, the Fleeting vocalization was analyzed in a mouse model (Tsc2+/-) of Autism Spectrum Disorder (ASD), and showed an abnormal persistence, in particular in females which presented delayed conversion of Fleeting into Complex vocalizations compared with males. The identification of this novel vocalization represents an important insight into the maturation of mouse vocal repertoire and may be used as a developmental milestone in studies on neurodevelopmental disorders with communication impairments.

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 Insight into Informant Discrepancies Regarding Psychosexual Functioning of Adolescents with and without Autism Spectrum Disorder

2019 ◽  
Vol 30 (2) ◽  
pp. 487-501
Author(s):  
Linda P. Dekker ◽  
Kirsten Visser ◽  
Esther J.M. Vegt ◽  
Athanasios Maras ◽  
Jan Ende ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Informant Discrepancies ◽  
Spectrum Disorder ◽  
Insight Into ◽  
Psychosexual Functioning

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.

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