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. 2024 Feb 12;14(1):89.
doi: 10.1038/s41398-024-02747-9.

Effect of parental adverse childhood experiences on intergenerational DNA methylation signatures from peripheral blood mononuclear cells and buccal mucosa

Sahra Mohazzab-Hosseinian  1 , Erika Garcia  2 , Joseph Wiemels  3 , Crystal Marconett  4   5   6   7   8 , Karina Corona  2 , Caitlin G Howe  9 , Helen Foley  2 , Shohreh F Farzan  2 , Theresa M Bastain  2 , Carrie V Breton  10
Affiliations

Effect of parental adverse childhood experiences on intergenerational DNA methylation signatures from peripheral blood mononuclear cells and buccal mucosa

Sahra Mohazzab-Hosseinian et al. Transl Psychiatry. .

Abstract

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 (N = 120) and neonatal cord blood (N = 69) samples. Replication in buccal samples was explored in the Children's Health Study (CHS) among adult parental (N = 31) and pediatric (N = 114) samples. 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 (N = 60 mother-child pairs) 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. CLCN7 was also nominally significant in the gene expression correlation analysis among maternal profiles (N = 35), along with 11 other genes. 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

The authors declare no competing interests.

Figures

Fig. 1
Fig. 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 higher in ACE groups versus the unexposed individuals, and red indicates a log-fold change with methylation lower in exposed versus unexposed individuals.
Fig. 2
Fig. 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 lower methylation in higher ACE scores compared to those with no ACEs.
Fig. 3
Fig. 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).
Fig. 4
Fig. 4. 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.
Fig. 5
Fig. 5. Boxplots of COMT effect in maternal PBMC and neonatal cord blood methylation.
Beta Values for COMT regional methylation in maternal PBMC and neonatal cord blood samples in MADRES.
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