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[Preprint]. 2023 Jun 26:rs.3.rs-2977515.
doi: 10.21203/rs.3.rs-2977515/v1.

Effect of Parental Adverse Childhood Experiences on Intergenerational DNA Methylation Signatures

Sahra Mohazzab-Hosseinian  1 , Erika Garcia  1 , Joseph Wiemels  1 , Crystal Marconett  1 , Karina Corona  1 , Caitlin Howe  1 , Helen Foley  1 , Deborah Lerner  1 , Nathana Lurvey  1 , Shohreh Farzan  1 , Theresa Bastain  1 , Carrie Breton  1
Affiliations

Effect of Parental Adverse Childhood Experiences on Intergenerational DNA Methylation Signatures

Sahra Mohazzab-Hosseinian et al. Res Sq. .

Update in

Abstract

Adverse Childhood Experiences (ACEs) are events that occur before a child turns 18 years old that may cause trauma. In this study, the effect of cumulative ACEs experienced on human maternal DNA methylation (DNAm) was estimated while accounting for interaction with domains of ACEs in prenatal peripheral blood mononuclear cell samples from the Maternal and Developmental Risks from Environmental Stressors (MADRES) pregnancy cohort. The intergenerational transmission of ACE-associated DNAm was also explored used paired maternal and neonatal cord blood samples. Replication in buccal samples was explored in the Children's Health Study (CHS). We used a four-level categorical indicator variable for ACEs exposure: none (0 ACEs), low (1-3 ACEs), moderate (4-6 ACEs), and high (> 6 ACEs). Effects of ACEs on maternal DNAm (N = 240) were estimated using linear models. To evaluate evidence for intergenerational transmission, mediation analysis was used. Analysis of maternal samples displayed some shared but mostly distinct effects of ACEs on DNAm across low, moderate, and high ACEs categories. CLCN7 and PTPRN2 was associated with maternal DNAm in the low ACE group and this association replicated in the CHS. ACE-associated methylation was observed in maternal and neonatal profiles in the COMT promoter region, with some evidence of mediation by maternal COMT methylation. Specific genomic loci exhibited mutually exclusive maternal ACE effects on DNAm in either maternal or neonatal population. There is some evidence for an intergenerational effect of ACEs, supported by shared DNAm signatures in the COMT gene across maternal-neonatal paired samples.

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Conflict of interest statement

Conflicts of Interest The authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1. Volcano Plots for the Effect of ACEs on Maternal DNA methylation
Top five p-value significant (FDR < 0.05) annotated genes for each ACEs category: none (0 ACEs), low (1–3 ACEs), moderate (4–6 ACEs), and high (>6 ACEs) are labelled. All red and blue dots are significant probes (FDR < 0.05), all black dots are those that did not meet FDR significance (FDR > 0.05). Blue indicates a log-fold change with methylation increased in ACE groups versus the control group, and red indicates a log-fold change with methylation decreased in exposed versus unexposed individuals.
Figure 2
Figure 2. Boxplots of Stable ACE effects in Significant Maternal Probes
Boxplot of beta values for Maternal CpG cg20656154 significant (FDR < 0.05) across higher ACE scores. There was a trend for decreased methylation in higher ACE scores compared to those with no ACEs.
Figure 3
Figure 3. Indirect Effect of ACEs on Intergenerational DNA methylation Signatures
Effect of Maternal ACEs on neonatal COMT methylation is partially (64%) mediated by maternal COMT methylation. This indirect effect was significant (p-value = 0.044) with a 95% CI of (0.0025,0.32)
Figure 4
Figure 4. Boxplots of COMT Effect in Maternal and Neonatal Samples
Beta Values for COMT regional methylation in maternal and neonatal samples in MADRES.
Figure 5
Figure 5. KEGG pathways in ACE-associated DMPs in Maternal Discovery Population
Significant (FDR < 0.05) maternal DMP genes in MADRES input to ShinyGO to generate KEGG pathways
See this image and copyright information in PMC

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