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Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis.

ABSTRACT: Background:Intermittent explosive disorder is defined as a recurrent, problematic, and impulsive aggression that affects 3% to 4% of the US population. While behavioral genetic studies report a substantial degree of genetic influence on aggression and impulsivity, epigenetic mechanisms underlying aggression and intermittent explosive disorder are not well known. Methods:The sample included 44 subjects (22 with a DSM-5 diagnosis of intermittent explosive disorder and 22 comparable subjects without intermittent explosive disorder). Peripheral blood DNA methylome was profiled using the Illumina Infinium HumanMethylation450 Beadchip. Intermittent explosive disorder-associated genome-wide DNA methylation changes were analyzed using the CpGassoc R package, with covariates age, sex, and race being adjusted. A gene-based functional enrichment analysis was performed to identify pathways that were overrepresented by genes harboring highly differentially methylated CpG sites. Results:A total of 27 CpG sites were differentially methylated in IED participants (P<5.0×10-5), but none reached genome-wide significant threshold. Functional enrichment analysis revealed that genes mapped by these CpG sites are involved in the inflammatory/immune system, the endocrine system, and neuronal differentiation. Conclusions:Consistent with our previous studies showing an association of inflammatory response with aggressive behavior in intermittent explosive disorder subjects, our gene-based pathway analysis using differentially methylated CpG sites supports inflammatory response as an important mechanism involved in intermittent explosive disorder and reveals other novel biological processes possibly associated with intermittent explosive disorder.

SUBMITTER: Montalvo-Ortiz JL

PROVIDER: S-EPMC5789263 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis.

Montalvo-Ortiz Janitza L JL Zhang Huiping H Chen Chao C Liu Chunyu C Coccaro Emil F EF

The international journal of neuropsychopharmacology 20180101 1

<h4>Background</h4>Intermittent explosive disorder is defined as a recurrent, problematic, and impulsive aggression that affects 3% to 4% of the US population. While behavioral genetic studies report a substantial degree of genetic influence on aggression and impulsivity, epigenetic mechanisms underlying aggression and intermittent explosive disorder are not well known.<h4>Methods</h4>The sample included 44 subjects (22 with a DSM-5 diagnosis of intermittent explosive disorder and 22 comparable ...[more]

PMID: 29106553

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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.

Dataset Information

Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis.

Publications

Genome-Wide DNA Methylation Changes Associated with Intermittent Explosive Disorder: A Gene-Based Functional Enrichment Analysis.

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