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

Charlotte A. M. Cecil, Esther Walton, Jean-Baptiste Pingault, Nadine Provencal, Irene Pappa, Frank Vitaro, Sylvana Cote, Moshe Szyf, Richard E. Tremblay, Henning Tiemeier, Essi Viding, Eamon J. McCrory

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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: (i) DNAm patterns in humans associate with physical aggression independently of other co-occurring psychiatric and behavioral symptoms; (ii) whether these patterns are observable across multiple tissues; and (iii) whether they may function as a causal vs non-causal biomarker of physical aggression. Here, we used a multi-sample, 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 vs 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.
Original languageEnglish
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Early online date9 Nov 2018
Publication statusE-pub ahead of print - 9 Nov 2018


  • DNA methylation
  • physical aggression
  • DRD4
  • externalizing problems
  • replication
  • Mendelian randomization


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