Epigenetic DNA modifications in genes related to the hypothalamic–pituitary–adrenal (HPA) axis are discussed as a mechanism underlying the association between prenatal depression and altered child HPA activity. In a longitudinal study, DNA methylation changes related to prenatal depressive symptoms were investigated in 167 children aged 6 to 9 years. At six candidate genes, 126 cytosine–guanine dinucleotides were considered without correcting for multiple testing due to the exploratory nature of the study. Further associations with the basal child HPA activity were examined. Children exposed to prenatal depressive symptoms exhibited lower bedtime cortisol (p = .003, η_p² = 0.07) and a steeper diurnal slope (p = .023, η_p² = 0.06). For total cortisol release, prenatal exposure was related to lower cortisol release in boys, and higher release in girls. Furthermore, prenatal depressive symptoms were associated with altered methylation in the glucocorticoid receptor gene (NR3C1), the mineralocorticoid receptor gene (NR3C2), and the serotonin receptor gene (SLC6A4), with some sex-specific effects (p = .012–.040, η_p² = 0.03–0.04). In boys, prenatal depressive symptoms predicted bedtime cortisol mediated by NR3C2 methylation, indirect effect = –0.07, 95% confidence interval [–0.16, –0.02]. Results indicate relations of prenatal depressive symptoms to both child basal HPA activity and DNA methylation, partially fitting a mediation model, with exposed boys and girls being affected differently.

In order to better understand the underpinnings of attention-deficit/hyperactivity disorder (ADHD), we targeted the relationship of attentional, cognitive control and motivational processes with DNA methylation patterns of 60 candidate genes in boys at early school age. Participants (6 to 8 years; N = 82) were selected from a German longitudinal cohort (FRANCES). ADHD-related behaviour was assessed via maternal ratings. Performance and event-related potential measures (inter alia Cue-P3 and Nogo-P3), which were recorded in a motivational go/nogo task, indicated diminished attentional orienting, reduced inhibitory response control and a larger motivational effect on performance in ADHD already at this relatively young age. Methylation patterns were analysed in buccal cell DNA with the Illumina HumanMethylation 450K array. For CpG sites at genes of the dopaminergic (COMT, ANKK1) and the neurotrophic (BDNF, NGFR) system, associations with the Nogo-P3 as well as ADHD symptom severity were found suggesting that these systems are involved in response control deficits in ADHD. Methylation effects related to both functional aspects and ADHD behaviour were also observed for DPP10 and TPH2. Epigenetic mechanisms may play a role in ADHD-associated deficits but findings need to be replicated in larger samples and are limited by the fact that only peripheral methylation could be considered.

Prenatal alcohol exposure (PAE) is known to elicit a broad range of systemic effects, including neurophysiological alterations that result in adverse behavioral and cognitive outcomes. However, molecular pathways underlying these long-term intrauterine effects remain to be investigated. Here, we tested a hypothesis that PAE may lead to epigenetic alterations to the DNA resulting in attentional and cognitive alterations of the children. We report the results of the study that included 156 primary school children of the Franconian Cognition and Emotion Studies (FRANCES) cohort which were tested for an objective marker of PAE, ethyl glucuronide (EtG) in meconium at birth. Thirty-two newborns were found to be exposed to alcohol with EtG values above 30 ng/g (EtG+). Previously we described PAE being associated with lower IQ and smaller amplitude of the event-related potential component P3 in go trials (Go-P3), which indicates a reduced capacity of attentional resources. Whole-genome methylation analysis of the buccal cell DNA revealed 193 differentially methylated genes in children with positive meconium EtG, that were clustered into groups involved in epigenetic modifications, neurodegeneration, neurodevelopment, axon guidance and neuronal excitability. Furthermore, we detected mediation effects of the methylation changes in DPP10 and SLC16A9 genes on the EtG related cognitive and attention-related deficits. Our results suggest that system-wide epigenetic changes are involved in long-term effects of PAE. In particular, we show an epigenetic mediation of PAE effects on cognition and attention-related processes.

Zusammenfassung. Die Schwangerschaft stellt einen Lebensabschnitt der Frau dar, der mit körperlichen und hormonellen Veränderungen sowie einer erhöhten emotionalen und psychischen Beanspruchung einhergeht. Für das Kind gilt die Zeit im Mutterleib dabei als besonders sensible Phase, in der ungünstige intrauterine Bedingungen sowohl die fetale als auch die postnatale Entwicklung und Gesundheit langfristig beeinflussen können. So haben sich Depression, Angst und Stress in der Schwangerschaft als Risikofaktoren für Entwicklungsverzögerungen sowie emotionale und Verhaltensauffälligkeiten erwiesen. Epigenetische Veränderungen, insbesondere die DNA-Methylierung, werden als Wirkmechanismus für den Einfluss pränataler affektiver Belastungen auf das Kind diskutiert. Diese Arbeit soll einen Überblick geben, welche Veränderungen in der kindlichen DNA-Methylierung mit affektiven Belastungen in der Schwangerschaft assoziiert sind. Dabei werden Ergebnisse aus genspezifischen und epigenomweiten Studien vorgestellt, Problemfelder diskutiert und Anregungen für zukünftige Fragestellungen gegeben.