Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes.
Autism Spectrum Disorder
/ diagnosis
Biomarkers
Brain
/ metabolism
Child, Preschool
Computational Biology
/ methods
DNA Methylation
Epigenesis, Genetic
Epigenome
Erythrocyte Count
Female
Fetal Blood
Gene Expression Regulation
Genes, X-Linked
Humans
Infant
Infant, Newborn
Machine Learning
Male
Neurogenesis
Organ Specificity
/ genetics
Prognosis
Autism spectrum disorder
DNA methylation
Epigenetics
Epigenome
Epigenome-wide association study
Neurodevelopment
Prospective study
Umbilical cord blood
Whole-genome bisulfite sequencing
X chromosome
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
14 10 2020
14 10 2020
Historique:
received:
05
06
2020
accepted:
25
09
2020
entrez:
15
10
2020
pubmed:
16
10
2020
medline:
4
8
2021
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33054850
doi: 10.1186/s13073-020-00785-8
pii: 10.1186/s13073-020-00785-8
pmc: PMC7559201
doi:
Substances chimiques
Biomarkers
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
88Subventions
Organisme : CIHR
ID : BPF-162684
Pays : Canada
Organisme : NICHD NIH HHS
ID : P50 HD103526
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES029213
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES017646
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD079125
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES023513
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES025574
Pays : United States
Organisme : NIEHS NIH HHS
ID : R24 ES028533
Pays : United States
Organisme : NIEHS NIH HHS
ID : P01 ES011269
Pays : United States
Organisme : CIHR
ID : MFE-146824
Pays : Canada
Organisme : NIEHS NIH HHS
ID : R01 ES016443
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES020392
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES025531
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD051958
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES028089
Pays : United States
Organisme : NIH HHS
ID : UG3 OD023365
Pays : United States
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