DNA methylation signature of human fetal alcohol spectrum disorder

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.

Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels

“…Additionally, emerging evidence of epigenetic changes due to prenatal alcohol exposure has been reported [57]. For example, distinct DNA methylation patterns observed in adolescents and children with FASD [73] may effect immune organ development and immune-related gene expressions.…”

Regulation of neural circuit formation by protocadherins

“…Though it remains to be demonstrated that reduced γ-Pcdh protein levels are causal for any of the dendritic or synaptic defects seen in DS, the phenotypes observed in Pcdhg null cortex (as discussed above, decreased dendrite arborization and altered dendritic spine number and morphology) are certainly consistent with such a possibility [54,82]. Studies exploring methylation patterns in FASD similarly discovered increased methylation of the clustered Pcdhs both in the brains of FASD mouse models and in buccal cells of human FASD patients [168,169]. …”

Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-related pathology

“…Also, lentiviral knockdown of MeCP2 normalized the decreases in Pomc and normalized the aberrant hormonal response to stress in fetal alcohol-exposed animals (Gangisetty, Bekdash, Maglakelidze, & Sarkar, 2014). Finally, DNA methylation is also differentially altered in human populations exposed to in utero alcohol, as a recent study of methylation status of buccal swabs from children with FASD showed hypermethylation in genes implicated in neurodevelopment and neurological diseases such as anxiety, epilepsy, and autism-spectrum disorders (Portales-Casamar et al, 2016). …”