Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study.
paper
Cited
Public
- Authors
- Cecil, C A M; Lysenko, L J; Jaffee, S R; Pingault, J-B; Smith, R G; Relton, C L; Woodward, G; McArdle, W; Mill, J; Barker, E D
- Year
- 2014
- Journal
- Molecular psychiatry
- PMID
- 25199917
- DOI
- 10.1038/mp.2014.95
- PMCID
- PMC4231290
Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU (genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth-age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth-age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.
Location of OXTR methylation probes and associations with CU traits. Panel A: Location of methylation probes within the CpG island (hg19; chr3:8808962–8811280) included in the study, and how these are grouped into factors (i.e. Factor 1: purple; Factor 2: blue; Factor 3: yellow). Black rectangles indicate the area of the OXTR CpG island investigated by previous research on DNA methylation. Significant CpG sites identified by these studies are shown as black circles. Numbering is relative to the translation start site (+1). Panel B: Association between Factor 2 methylation and CU traits for youth with low (INT−) vs high (INT+) co-occurring levels of internalizing problems, across time points.
Levels of CU traits and environmental risk exposure across groups. Panel A: Standardized mean levels of CU and descriptives for INT− vs INT+. Panel B: Standardized mean levels of environmental risk exposure across individual domains and developmental eras for INT− vs INT+.
Integrative developmental model. Panel A: INT− group. Panel B: INT+ group. Single arrowed lines indicate standardized path coefficients that survived bootstrap-corrected confidence intervals (i.e. significant path). Red arrows show significant individual risk domains based on post-hoc analyses. Dotted arrowed lines indicate non-significant paths. Population effect sizes are interpreted using the standardized estimates (Std. B) following Cohen’s guidelines: an effect of .10 is small effect, an effect of .24 is a medium effect, and an effect of .37 is a large effect.
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