Abstract
BackgroundPrenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 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.MethodsGenome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in 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.ResultsAfter correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders.ConclusionsThese findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0074-4) contains supplementary material, which is available to authorized users.
Highlights
Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America
In order to ascertain the effect of prenatal alcohol exposure (PAE) on the human epigenome, the present study investigated the DNA methylation patterns of buccal epithelial cell (BEC) from 110 children with fetal alcohol spectrum disorder (FASD) and 96 age- and sex-matched controls, to our knowledge representing the largest investigation on PAE effects on the human epigenome
The NeuroDevNet FASD epigenetics cohort Participants in the NeuroDevNet Canadian FASD study cohort were recruited from six clinical sites across Canada (Vancouver, BC; Edmonton, AB; Cold Lake, AB; Winnipeg, MB; Ottawa, ON; and Kingston, ON) [39]
Summary
Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 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). 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. The most studied epigenetic modification in human populations is DNA methylation, which refers to the covalent attachment of a methyl group to the 5′ position of cytosine, typically occurring in the context of cytosine–guanine dinucleotide (CpG) sites [11]. The 2-kb regions flanking CGIs are known as CGI “shores,” while the areas located beyond shores are known as “shelves” [13,14,15] Of note, these regions are typically more variable than CGIs themselves, as they have a greater range of DNA methylation across individuals [14]. There are a number of possible reasons for this association, including shared environments or associations of epigenetic marks with specific genetic variants [22,23,24]
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