Epigenetic profiling of Fetal Alcohol Spectrum Disorder (FASD) Discovery
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ABSTRACT:
PROVIDER: PRJNA449694 | ENA |
REPOSITORIES: ENA
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Project description:Background: Fetal alcohol spectrum disorder (FASD) is a developmental disorder that manifests through a range of cognitive, adaptive, physiological, and neurobiological deficits resulting from prenatal alcohol exposure. Although the North American prevalence is currently estimated at 2-5%, FASD has proven difficult to identify in the absence of the overt physical features characteristic of fetal alcohol syndrome. As interventions may have the greatest impact at an early age, accurate biomarkers are needed to identify children at risk for FASD. Building on our previous work identifying distinct DNA methylation patterns in children and adolescents with FASD, we have attempted to validate these associations in a different clinical cohort and to use our DNA methylation signature to develop a possible epigenetic predictor of FASD. Methods: Genome-wide DNA methylation patterns were analyzed using the Illumina HumanMethylation450 array in the buccal epithelial cells of a cohort of 48 individuals aged 3.5-18 (24 FASD cases, 24 controls). The DNA methylation predictor of FASD was built using a stochastic gradient boosting model on our previously published dataset FASD cases and controls (GSE80261). The predictor was tested on the current dataset and an independent dataset of 48 autism spectrum disorder cases and 48 controls (GSE50759). Results: We validated findings from our previous study that identified a DNA methylation signature of FASD, replicating the altered DNA methylation levels of 161/648 CpGs in this independent cohort, which may represent a robust signature of FASD in the epigenome. We also generated a predictive model of FASD using machine learning in a subset of our previously published cohort of 179 samples (83 FASD cases, 96 controls), which was tested in this novel cohort of 48 samples and resulted in a moderately accurate predictor of FASD status. Upon testing the algorithm in an independent cohort of individuals with autism spectrum disorder, we did not detect any bias towards autism, sex, age, or ethnicity. Conclusion: These findings further support the association of FASD with distinct DNA methylation patterns, while providing a possible entry point towards the development of epigenetic biomarkers of FASD.
2018-02-23 | GSE109042 | GEO
Project description:Epigenetic profiling of Fetal Alcohol Spectrum Disorder (FASD)
| PRJNA449761 | ENA
Project description:Prenatal alcohol exposure is the leading preventable cause of behavioural and cognitive deficits, which may affect between 2-5% of children in North America. While the underlying mechanisms of alcohol’s effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with Fetal Alcohol Spectrum Disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date. Genome-wide DNA methylation patterns of buccal epithelial cells were analyzed using the Illumina HumanMethylation450 array on a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip. After correcting for the effects of genetic background, 658 significantly differentially methylated sites between FASD cases and controls remained, with 41 displaying differences in beta greater than 5%. Furthermore, 203 differentially methylated regions containing 2 or more CpGs were also identified, overlapping with 167 different genes. The majority of differentially methylated genes were highly expressed in samples from the Allen Brain Atlas, which showed high correlations with buccal cell DNA methylation patterns. Furthermore, over-representation analysis of the up-methylated genes displayed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders. These findings suggest that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.
2017-04-13 | GSE80261 | GEO
Project description:Epigenetic profiling of Fetal Alcohol Spectrum Disorder (FASD) Replication
| PRJNA449759 | ENA
Project description:The Illumina Human Omni2.5 array is a high resolution microarray platform for studying copy number variations in the human genome. It is widely being used in both clinical and research settings for identifying causative variants as well as interrogating the genome for benign variants. We employed this platform to investigate the risk factor CNVs in 95 individuals diagnosed with Fetal alcohol spectrum syndrome (FASD). We also examined 87 age-matched individuals with no symptoms of FASD or any neurodevelopmental disorders. We compared their CNVs to those of 10,851 population controls, in order to identify rare CNVs (<0.1% frequency) that might be relevant to FASD.
2018-11-21 | GSE102650 | GEO
Project description:Genome wide DNA methylation profiling of FASD patients versus healthy unexposed controls. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 485,000 CpGs in peripheral blood samples. Samples included 64 healthy controls and 39 FASD patients.
2019-03-18 | GSE112987 | GEO
Project description:This study examined if p53 was essential in the brain’s response to alcohol using a mouse model of fetal alcohol spectrum disorder (FASD) that involved the equivalent of a single day of binge drinking. We quantified the amount of cell death in specific brain regions and examined the levels of gene expression in these regions 8 hours after alcohol exposure using RNA-seq. Contrary to expectations, we found that cell death still occurred at the same or greater level in the brains of mice lacking p53 as in normal mice. However, we also found evidence that the lack of p53 greatly affected the expression of groups of genes involved in brain cell communication and metabolism.
2017-09-05 | GSE100217 | GEO
Project description:Fetal alcohol spectrum disorders (FASD) are common, seen in 1-5% of the population in the United States and Canada. Regrettably, children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood. We have modeled FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We report an association between adult hippocampal gene expression and prenatal and postnatal treatment that is related to behavioral changes. Clustering of expression profiles through weighted gene co-expression network analysis (WGCNA) identifies a set of transcripts associated with anxiety-like behavior as well as treatment group. Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation. Together, transcriptional control is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Greater understanding of the role of prenatal alcohol exposure and postnatal stress in altering the hippocampal transcriptome in the hippocampus is warranted. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.
2019-06-27 | GSE133369 | GEO
Project description:Alcohol preferring vervet dams were permitted to ingest alcohol 4 days/week during the second half of gestation (e90-e165) and paired with sucrose matched controls. Cases and controls were sacrificed with subsequent hippocampal extraction at 5 months and 2 years. RNA was extracted according to the manufacturer's protocol and hybridized to the Affymetrix Rhesus Genechip microarray. We sought to identify whether global downregulation in mRNA dataset was related to miRNA expression in a non-human primate model of FASD in order to develop an understanding of how this disorder may develop in humans.
2022-01-24 | GSE181456 | GEO
Project description:Alcohol preferring vervet dams were permitted to ingest alcohol 4 days/week during the second half of gestation (e90-e165) and paired with sucrose matched controls. Cases and controls were sacrificed with subsequent hippocampal extraction at 5 months and 2 years. RNA was extracted according to the manufacturer's protocol and hybridized to the Affymetrix Rhesus Genechip microarray. We sought to identify pathways and genes involved in the development of fetal alcohol spectrum disorder in a non-human primate in order to develop an understanding of how this disorder may develop in humans.
2022-02-23 | GSE173516 | GEO