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 Provençal, Irene Pappa, Frank Vitaro, Sylvana Côté, Moshe Szyf, Richard E Tremblay, Henning Tiemeier, Essi Viding, Eamon J McCrory

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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 co-occurring 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.

Original languageEnglish
Pages (from-to)746-764
Number of pages19
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume177
Issue number8
Early online date9 Nov 2018
DOIs
Publication statusPublished - Dec 2018

Keywords

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

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    Cecil, C. A. M., Walton, E., Pingault, J-B., Provençal, N., Pappa, I., Vitaro, F., Côté, S., Szyf, M., Tremblay, R. E., Tiemeier, H., Viding, E., & McCrory, E. J. (2018). DRD4 methylation as a potential biomarker for physical aggression: An epigenome-wide, cross-tissue investigation. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 177(8), 746-764. https://doi.org/10.1002/ajmg.b.32689