Citation

Cecil CAM, Walton E, Pingault JB, Provençal N, Pappa I, Vitaro F, Côté S, Szyf M, Tremblay RE, Tiemeier H, Viding E, McCrory EJ. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2018; 177(8): 746-764.

Affiliation

Division of Psychology and Language Sciences, University College London, London, United Kingdom.

Copyright

(Copyright © 2018, John Wiley and Sons)

DOI

10.1002/ajmg.b.32689

PMID

30411855

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.

© 2018 Wiley Periodicals, Inc.

Language: en

Keywords

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