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

Abstract

BackgroundIntermittent 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.MethodsThe 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.ResultsA 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.ConclusionsConsistent 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.

DRD4 methylation as a potential biomarker for physical aggression: An epigenome‐wide, cross‐tissue investigation

“…One of these was “hormone metabolic processes,” with several high‐ranking DMPs annotated to thyroid hormone pathway genes ( TRH, FDX1, TNX2, and TXNRD2 ), consistent with prior evidence of thyroid hormone dysregulation in pathological aggression in humans (Evrensel, Ünsalver, & Özşahin, ) and attack behavior in mice (Hrabovszky et al, ). Another set of enriched pathways related to inflammatory processes, including “cytokine secretion.” This is in line with reported alterations in DNAm and expression levels of cytokine genes in individuals with a chronic history of childhood physical aggression (Provençal, Suderman, Caramaschi, et al, ; Provencal, Suderman, Vitaro, Szyf, & Tremblay, ), as well as in individuals diagnosed with IED (Montalvo‐Ortiz et al, ). We also identified enrichment for multiple CNS‐related processes, such as “Axon guidance.” Interestingly, this same GO pathway was found to be highly enriched in the EWAS study on global aggression by van Dongen et al () as well as a recent bioinformatic analysis combining findings from six GWAS studies on aggression‐related phenotypes (Fernàndez‐Castillo & Cormand, ).…”

“…However, a gene ontology analysis identified significant enrichment for genes involved in a range of central nervous system processes. As would be expected for brain‐based phenotypes, epigenetic alterations in genes involved in neural function have also been observed in psychiatric disorders that feature aggression as a diagnostic criterion, such as childhood disruptive behavior disorders (Barker et al, ; Cecil et al, ), IED (Montalvo‐Ortiz, Zhang, Chen, Liu, & Coccaro, ), and ASPD (Beach, Brody, Todorov, Gunter, & Philibert, ; Checknita et al, ).…”

Theorizing the Role of Dopaminergic Polymorphic Risk Alleles with Intermittent Explosive Disorder (IED), Violent/Aggressive Behavior and Addiction: Justification of Genetic Addiction Risk Severity (GARS) Testing

“…Puhalla et al showed that IED, aggression frequency, AUD, and childhood abuse were all independently associated with overall aggression; however, only individuals with IED displayed increased intoxicated aggression related to the degree of AUD severity [7]. Therefore, genetic vulnerability could be one possible neurobiological basis for this type of behavior [8]. For example, a history of childhood abuse could enhance the frequency of engaging in overall aggression and developing IED, which may increase the association between SUD severity and well-known intoxicated aggression.…”