Journal
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS
Volume 177, Issue 8, Pages 746-764Publisher
WILEY
DOI: 10.1002/ajmg.b.32689
Keywords
DNA methylation; DRD4; externalizing problems; Mendelian randomization; physical aggression; replication
Categories
Funding
- Economic and Social Research Council [ES/N001273/1]
- Waterloo Foundation [R1233/1872]
- Quebec Research Fund for Society and Culture
- Social Sciences and Humanities Research Council of Canada
- Canadian Institutes for Health Research
- Quebec Research Fund for Health
- BBSRC [BB/I025263/1] Funding Source: UKRI
- ESRC [ES/N000498/1, ES/N001273/1] Funding Source: UKRI
- MRC [MC_UU_00011/5, MC_UU_12013/2] Funding Source: UKRI
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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: (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.
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