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

Abstract

Epigenetic processes that regulate gene expression, such as DNA methylation (DNAm), have been linked to individual differences in physical aggression. Yet, it is currently unclear whether:(a) DNAm patterns in humans associate with physical aggression independently of other cooccurring psychiatric and behavioral symptoms; (b) whether these patterns are observable across multiple tissues; and (c) whether they may function as a causal versus noncausal biomarker of physical aggression. Here, we used a multisample, cross-tissue design to address these questions. First, we examined genome-wide DNAm patterns (buccal swabs; Illumina 450k) associated with engagement in physical fights in a sample of high-risk youth (n = 119; age = 16-24 years; 53% female). We identified one differentially methylated region in DRD4, which survived genome-wide correction, associated with physical aggression above and beyond co-occurring symptomatology (e.g., ADHD, substance use), and showed strong cross-tissue concordance with both blood and brain. Second, we found that DNAm sites within this region were also differentially methylated in an independent sample of young adults, between individuals with a history of chronic-high versus low physical aggression (peripheral T cells; ages 26-28). Finally, we ran a Mendelian randomization analysis using GWAS data from the EAGLE consortium to test for a causal association of DRD4 methylation with physical aggression. Only one genetic instrument was eligible for the analysis, and results provided no evidence for a causal association. Overall, our findings lend support for peripheral DRD4 methylation as a potential biomarker of physically aggressive behavior, with no evidence yet of a causal relationship. K E Y W O R D S DNA methylation, DRD4, externalizing problems, Mendelian randomization, physical aggression, replication † Co-senior authors.

Genome-Wide DNA Methylation Patterns in Persistent Attention-Deficit/Hyperactivity Disorder and in Association With Impulsive and Callous Traits

“…Up to now, no EWAS investigated the clinical persistence of ADHD into adulthood, representing a lack of hypothesis-generating studies of potential epigenetics-related molecular mechanisms of persistence/ remittance of ADHD. Similar to the situation for ADHD, only few previous EWASs investigated the association of DNA methylation and impulsive and aggressive traits, and those involved general population samples, only (van Dongen et al, 2015;Cecil et al, 2018;Montalvo-Ortiz et al, 2018).…”

From Genotype to Phenotype: Through Chromatin

“…However, since DNA methylation can be both an inducer and the outcome of the disease, MR with epigenetic data needs to be used with caution [93]. Nevertheless, the remarkably simple idea behind the MR allows researchers to make very interesting claims, studying causality between the epigenetic marks and a wide range of outcomes, from blood lipid levels [94] through features such as physical aggression [95]. Used together with EWAS and GWAS analyses, MR gives us the possibility to propose biomarker loci or targets for therapies for patients [82].…”

Using Openly Accessible Resources to Strengthen Causal Inference in Epigenetic Epidemiology of Neurodevelopment and Mental Health

“…However, in some instances, conflicting evidence can be found [6] or only very weak evidence is provided, as seen in a study on post-traumatic stress and major depressive disorder [7]. With respect to neurodevelopment, DNA methylation differences were reported in relation to educational attainment and cognitive abilities measured in adulthood [8], attention-deficit hyperactivity disorder [9], oppositional defiant disorder [10], multiple risk behaviours [11], substance abuse [12], early-onset conduct disorder [13] and childhood physical aggression [14], with weaker evidence for an association with violent aggression and diagnosed autism spectrum disorders [15,16,17]. Neurological conditions that showed differences in blood-based DNA methylation when compared to controls include mesial temporal lobe epilepsy [18], narcolepsy [19] and Parkinson’s disease [20].…”

“…Following this strategy, two-sample MR has recently been applied to test for a causal effect of methylation in the DRD4 gene on physical aggression and did not support a causative link [14].…”