DNA methylation as a predictor of fetal alcohol spectrum disorder

Abstract

BackgroundFetal 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.MethodsGenome-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).ResultsWe 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.ConclusionThese 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.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0439-6) contains supplementary material, which is available to authorized users.

Fetal Alcohol Spectrum Disorder: Risk for Diabetes and Congenital Heart Defects

“…The few studies that have measured cardiac function in FASD animal models support the hypothesis that CHDs arising from ethanol exposure could have a significant contribution from abnormal function [26]. Abnormal embryonic cardiac function (as well as abnormal valves) was identified through ultrasound and histology, respectively at late stages (embryonic day 15.5) [italics researchers] of mouse development after ethanol exposure at gastrulation [27,28]. Functional and structural defects, including anomalies in heart volume/ morphology and conduction, were observed in latestage zebrafish after ethanol exposure, thus mimicking malformations occurring in patients with FASD [29].…”

“…As interventions may have the greatest impact at an early age, Salmon postulates that accurate biomarkers are needed to identify children at risk for FASD. Consequently, DNA methylation signature is being used to develop a possible epigenetic predictor of FASD [10,27]. However, despite the fact that alcohol was identified as a teratogen many decades ago, recent data indicate that in the US over 500,000 women per year report drinking during pregnancy with one in five of this population admitting to binge drinking [27].…”

“…Consequently, DNA methylation signature is being used to develop a possible epigenetic predictor of FASD [10,27]. However, despite the fact that alcohol was identified as a teratogen many decades ago, recent data indicate that in the US over 500,000 women per year report drinking during pregnancy with one in five of this population admitting to binge drinking [27]. Salmon also reports binge drinking by many of the women in her NZ study, some of whom were not aware that they were pregnant at the time [10].…”

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

“…Methylome changes have also been observed in individuals with FASD (Krishnamoorthy et al, ; Portales‐Casamar et al, ). These alterations in DNA methylation are being characterized as possible biomarkers to diagnose FASD (Legault, Bertrand‐Lehouillier, & McGraw, ; Lussier et al, ; Portales‐Casamar et al, ).…”

“…As folate is the main methyl group donor in the cell, this ethanol-induced reduction could affect many methylation reactions (Salbaum & Kappen, 2012). To date, there is no mechanism, biochemical, molecular or enzymatic that could explain this reduction in folate, although ethanol has been shown to also induce changes in the transport of folate (Legault, Bertrand-Lehouillier, & McGraw, 2018;Lussier et al, 2018;Portales-Casamar et al, 2016).…”