Changes in neuronal genes in prenatally alcohol-exposed placentas associate 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 (3'mRNA sequencing) analyses in 87 PAE, 77 unexposed control, and 11 only smoking-exposed 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 the age of six, numerous associations were observed for DNAm and gene expression with head circumference as well as cognitive performance, ADHD, and dysmorphology scores. Among the phenotype-associated genes were NR2F1, GPHN, GLI3, and FRZB, which are involved in neurogenesis and cortical patterning, postsynaptic clustering of GABA receptors, brain and craniofacial development, and regulation of Wnt signaling, respectively. As these alterations were detected in the placenta, this tissue not only enables the identification of phenotype-specific FASD candidate genes but may also provide a unique window into the developmental mechanisms underlying complex neurodevelopmental and dysmorphological disorders.