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

Mordaunt, Charles E.; Jianu, Julia M.; Laufer, Benjamin I.; Zhu, Yihui; Dunaway, Keith W.; Bakulski, Kelly M.; Feinberg, Jason I.; Volk, Heather E.; Lyall, Kristen; Croen, Lisa; Newschaffer, Craig J.; Ozonoff, Sally J; Hertz‐Picciotto, Irva; Fallin, M. Daniele; Schmidt, Rebecca J.; LaSalle, Janine M.

doi:10.1101/850529

Cited by 17 publications

(24 citation statements)

References 110 publications

(112 reference statements)

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“…The complementary co‐expression network analysis further revealed a module of 224 co‐expressed genes in maternal blood showing an association with folic acid and 5‐MeTHF levels in the opposite direction from ASD risk that could not be explained by cell type differences. Interestingly, these ASD and nutrient associated genes were functionally enriched for DNA methylation binding and methylation‐dependent chromatin silencing, consistent with prior DNA methylation changes observed in ASD [Coulson et al, 2018; Mordaunt et al, 2020; Vogel Ciernia et al, 2019; Zhu et al, 2019] as well as ASD‐like syndromes associated with methyl binding proteins [Cukier et al, 2012; Cukier et al, 2010]. MBD3L , which has methyl‐binding function, is predicted to assist with demethylation reactions and functions as a transcriptional repressor [Fouse, Nagarajan, & Costello, 2010; Mungall, 2002; Zhou et al, 2019].…”

Section: Discussionsupporting

confidence: 82%

Expression Changes in Epigenetic Gene Pathways Associated With One‐Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non‐Typical Neurodevelopment

et al. 2020

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The prenatal period is a critical window for the development of autism spectrum disorder (ASD). The relationship between prenatal nutrients and gestational gene expression in mothers of children later diagnosed with ASD or non‐typical development (Non‐TD) is poorly understood. Maternal blood collected prospectively during pregnancy provides insights into the effects of nutrition, particularly one‐carbon metabolites, on gene pathways and neurodevelopment. Genome‐wide transcriptomes were measured with microarrays in 300 maternal blood samples in Markers of Autism Risk in Babies‐Learning Early Signs. Sixteen different one‐carbon metabolites, including folic acid, betaine, 5′‐methyltretrahydrofolate (5‐MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non‐TD and ASD, and to one‐carbon metabolites. Using differential gene expression analysis, six transcripts (TGR‐AS1, SQSTM1, HLA‐C, and RFESD) were associated with child outcomes (ASD, Non‐TD, and TD) with genome‐wide significance. Genes nominally differentially expressed between ASD and TD significantly overlapped with seven high confidence ASD genes. WGCNA identified co‐expressed gene modules significantly correlated with 5‐MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a suggestive protective association with folic acid/5‐MeTHF concentrations and ASD risk. Maternal plasma betaine and DMG concentrations were associated with a block of co‐expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. These results suggest that the prenatal maternal blood transcriptome is a sensitive indicator of gestational one‐carbon metabolite status and changes relevant to children's later neurodevelopmental outcomes. Lay Summary Pregnancy is a time when maternal nutrition could interact with genetic risk for autism spectrum disorder. Blood samples collected during pregnancy from mothers who had a prior child with autism were examined for gene expression and nutrient metabolites, then compared to the diagnosis of the child at age three. Expression differences in gene pathways related to the immune system and gene regulation were observed for pregnancies of children with autism and non‐typical neurodevelopment and were associated with maternal nutrients.

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Section: Discussionsupporting

confidence: 82%

Expression Changes in Epigenetic Gene Pathways Associated With One‐Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non‐Typical Neurodevelopment

et al. 2020

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“…The datasets supporting the conclusions of this article are available in the Gene Expression Omnibus repository at accession number GSE140730 [119]. All code used in the analyses for this study is available on GitHub [51].…”

Section: Abbreviationsmentioning

confidence: 99%

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

et al. 2020

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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.

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“…Comparison of the DMR- *Negative logarithm of the Fisher exact p-value indicating the probability that the indicated pathway is not enriched among the indicated genes based on the reference set of genes in the IPA Knowledgebase associated genes from the ASD and Faroese cord blood studies showed no significant overlap (Q = 0.84), but both sets of DMRs were highly enriched in genes on the X-chromosome. Intriguingly, the X-linked genes from the ASD cord blood were predominantly found in females (62), while those from the Faroese cord blood were exclusively male specific (61). By comparison, despite the highly significant overlap between the DMR-associated genes in the Faroese sperm and the ASD cord blood, there were relatively few X-linked DMR-associated genes found in sperm.…”

Section: Comparison Of Dmr-associated Genes From This Study With Thosmentioning

confidence: 88%

Impact of exposures to persistent endocrine disrupting compounds on the sperm methylome in regions associated with neurodevelopmental disorders

Maggio

Shu

Laufer

et al. 2021

Preprint

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Background: Although autism spectrum disorder (ASD) is among the most heritable of neurodevelopmental disorders, the rapidly rising prevalence of ASD suggests that environmental factors may contribute to epigenetic modifications that can influence risk for ASD. Endocrine disrupting compounds (EDCs), such as the long-lived organochlorines, are of particular interest with respect to risk for autism because of their ability to interfere with sex hormones that have been implicated in ASD. Methods: Whole genome bisulfite sequencing was used to identify genome-wide differentially methylated regions (DMRs) in a total of 52 sperm samples from a cohort of Faroese men who were equally divided into high and low exposure groups based on their serum levels of the long-lived organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE). Inhabitants of the Faroe Islands, who as a group are considered a genetic isolate, may be exposed to higher than average levels of such persistent EDCs because of their native diet that is enriched in pilot whale meat and blubber. Gene ontology and pathway analyses were used to determine enrichment in ASD-relevant pathways and functions among the DMR-associated genes. Results: DMRs were enriched in autism risk genes and could also discriminate between samples in high and low exposure groups. Functional and pathway analyses of these DMR-associated genes show significant enrichment for neurodevelopmental processes frequently impacted by ASD. Of note, the DMR-associated genes significantly overlap with those previously identified in sperm from fathers of children with ASD versus fathers of neurotypical children, thus suggesting a potential environmental mechanism for introducing ASD-associated epigenetic changes in the sperm methylome. Limitations: A limitation of this study is the relatively low number of samples, although this is somewhat offset by the use of a genetic isolate which reduces the genetic heterogeneity that is often a major challenge in epigenetic studies. Another limitation is the lack of a completely unexposed set of samples for comparisons since persistent EDCs can be detected in a majority of individuals. Conclusion: Results of this study show that elevated exposure to certain organochlorines is associated with genome-wide DNA methylation patterns in sperm affecting genes involved in neurological functions and developmental disorders, including ASD.

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

Cited by 17 publications

References 110 publications

Expression Changes in Epigenetic Gene Pathways Associated With One‐Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non‐Typical Neurodevelopment

Expression Changes in Epigenetic Gene Pathways Associated With One‐Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non‐Typical Neurodevelopment

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

Impact of exposures to persistent endocrine disrupting compounds on the sperm methylome in regions associated with neurodevelopmental disorders

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