Changes in neuronal genes in prenatally alcohol-exposed placentas correlate with neuropsychological traits at the age of six

Prenatal alcohol exposure (PAE) disrupts embryonic development and gives rise to a variable fetal alcohol spectrum disorder (FASD) phenotype characterized by neurodevelopmental and dysmorphological defects. We investigated the effects of PAE on placental gene regulation by performing genome-wide DNA methylation (DNAm) microarray and gene expression (mRNA sequencing) analyses in 87 PAE, 77 unexposed control, and 11 smoking-exposed-only placentas. Significant alterations were identified in genes involved in synaptic function including both excitatory and inhibitory neurotransmission, and in genes previously associated with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, schizophrenia, and addiction. When placental molecular alterations were compared with neuropsychological and dysmorphological phenotypes of the same children assessed at six years of age, numerous correlations were observed between DNAm and gene expression, as well as head circumference, cognitive performances, ADHD traits, and dysmorphology. These included associations between DAOA methylation and verbal intellectual abilities and language development, GPHN methylation and working memory index, and GLI3 expression and both working memory index and midfacial hypoplasia. As these alterations were observed in the placenta, this tissue not only enables the identification of phenotype-specific FASD candidate genes but also represents a valuable tool for studying complex developmental disorders in human.