Dataset Information

Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study.

ABSTRACT: Early-onset conduct problems (CP) are a key predictor of adult criminality and poor mental health. While previous studies suggest that both genetic and environmental risks play an important role in the development of early-onset CP, little is known about potential biological processes underlying these associations. In this study, we examined prospective associations between DNA methylation (cord blood at birth) and trajectories of CP (4-13 years), using data drawn from the Avon Longitudinal Study of Parents and Children. Methylomic variation at seven loci across the genome (false discovery rate < 0.05) differentiated children who go on to develop early-onset (n = 174) versus low (n = 86) CP, including sites in the vicinity of the monoglyceride lipase (MGLL) gene (involved in endocannabinoid signaling and pain perception). Subthreshold associations in the vicinity of three candidate genes for CP (monoamine oxidase A [MAOA], brain-derived neurotrophic factor [BDNF], and FK506 binding protein 5 [FKBP5]) were also identified. Within the early-onset CP group, methylation levels of the identified sites did not distinguish children who will go on to persist versus desist in CP behavior over time. Overall, we found that several of the identified sites correlated with prenatal exposures, and none were linked to known genetic methylation quantitative trait loci. Findings contribute to a better understanding of epigenetic patterns associated with early-onset CP.

SUBMITTER: Cecil CAM

PROVIDER: S-EPMC7612607 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study.

Cecil Charlotte A M CAM Walton Esther E Jaffee Sara R SR O'Connor Tom T Maughan Barbara B Relton Caroline L CL Smith Rebecca G RG McArdle Wendy W Gaunt Tom R TR Ouellet-Morin Isabelle I Barker Edward D ED

Development and psychopathology 20170609 2

Early-onset conduct problems (CP) are a key predictor of adult criminality and poor mental health. While previous studies suggest that both genetic and environmental risks play an important role in the development of early-onset CP, little is known about potential biological processes underlying these associations. In this study, we examined prospective associations between DNA methylation (cord blood at birth) and trajectories of CP (4-13 years), using data drawn from the Avon Longitudinal Stud ...[more]

PMID: 28595673

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Project description:ObjectiveThe aims of this study were to examine whether dispositional interpersonal callousness, negative emotionality, and hyperactivity/impulsivity uniquely influence the development of childhood-onset conduct problems and persistent criminal behavior in males, and to determine whether specific facets of negative emotionality (dysregulated anger versus anxiety) in childhood are differentially associated with the development of chronic antisocial behavior.MethodChildhood dispositional features and conduct problems were assessed semiannually using parent- and teacher-report measures across 9 consecutive assessments in a school-based sample of 503 boys (∼7-11 years of age). Participants' criminal behavior was assessed using official records from adolescence into the early 30s.ResultsInterpersonal callousness, dysregulated anger, and hyperactivity/impulsivity were uniquely associated with the development of childhood-onset conduct problems. None of these features significantly predicted official records of juvenile offending after controlling for co- occurring conduct problems. However, interpersonal callousness was robustly and uniquely associated with a pattern of persistent and violent adult offending that continued into the early 30s. In contrast, anxiety problems were inversely associated with criminal offending in adolescence and adulthood after controlling for conduct problems and the other dispositional factors.ConclusionFindings are consistent with theoretical models indicating that interpersonal callousness, dysregulated anger, and hyperactivity/impulsivity influence the development of childhood conduct problems. In contrast, anxiety problems in childhood tend to reduce the likelihood that boys will engage in later criminal offending. Results suggest that delinquency prevention programs should target children exhibiting features of interpersonal callousness, given that they are at high risk for engaging in chronic and violent offending in adulthood.

Project description:BackgroundEarly life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies.MethodsTo this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects.ResultsWe found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements.ConclusionsThese data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life.

Project description:Although selection of the early age at puberty in gilts will make for a favorable effect on the reproductivity of sow, a large proportion of phenotypic variation in age at puberty of gilts cannot be explained by genetics. Previous studies have implicated hypothalamic DNA methylation in the onset of puberty in mammals. However, the underlying molecular mechanism regarding the regulation of the onset of puberty has remained largely unexplored in gilts. Herein, the genome-scale DNA methylation of hypothalamus was acquired, using the reduced representation bisulfite sequencing, to compare and describe the changes of DNA methylation across Pre-, In- and Post-pubertal gilts. In this study, the average methylation levels of CpGs and CpHs (where H = C, T, or A) in CpG islands- and gene-related regions were gradually decreased in hypothalamic methylomes during the pubertal transition. Comparisons of Pre- vs. In-, In- vs. Post-, and Pre- vs. Post-pubertal stage revealed that there were 85726, 92914, and 100421 differentially methylated CpGs and 5940, 14804, and 16893 differentially methylated CpHs (where H = C, T, or A) in the hypothalamic methylomes. The methylation changes of CpHs were more dynamic than that of CpGs, and methylation changes of CpGs and CpHs were likely to be, respectively, involved in the developmental processes of reproduction and the molecular processes of cellular communications in the hypothalamus. Moreover, methylation changes of CpHs were observed to overrepresent in the quantitative trait loci of age at puberty, and the biological function of these CpH methylation changes was enriched in the pancreas development in gilts. Furthermore, the mRNA levels of several differentially CpG or CpH methylated genes related to the transcription of RNA II polymerase, GnRH signaling pathway, Estrogen signaling pathway, PI3K-AKt signaling pathway, and Insulin signaling pathway, including MAX, MMP2, FGF11, IGF1R, FGF21, and GSK3B, were significantly changed across these pubertal stages in the hypothalamus. These results will help our understanding of how DNA methylation contributes to phenotypic variation of age at puberty.

Dataset Information

Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study.

Publications

Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study.

Similar Datasets

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