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Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study.

Cecil CA, Lysenko LJ, Jaffee SR, Pingault JB, Smith RG, Relton CL, Woodward G, McArdle W, Mill J, Barker ED - Mol. Psychiatry (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Psychiatry, King's College London, London, UK.

ABSTRACT
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.

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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.
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Figure 1: 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.

Mentions: We extracted probes located within the OXTR CpG island (n = 12), as this area has been previously investigated by Dadds et al (10; see Figure 1, Panel A) and others (13, 21, 22), and shown to play a key role in modulating the transcriptional activity of OXTR (23). For each probe, methylation levels were indexed by beta values (corresponding to the ratio of methylated signal divided by the sum of the methylated and unmethylated signal). Factor analysis was used to reduce the 12 OXTR probes into a smaller set of factors, which accounted for shared variance between them (24). A 3-factor solution (see Figure 1A) showed the best fit to the data as well as good temporal stability. Full details of the factor analysis procedure and results are provided as an online supplement (SI 2–5). We present findings relating specifically to Factor 2 (3 probes located on Exon 2), because (i) Factor 1 did not associate with CU at any time point in either youth with low or high internalizing problems, and (ii) Factor 3 variance was not significant at any time point, thereby precluding the examination of associations with environmental risk and CU traits.


Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study.

Cecil CA, Lysenko LJ, Jaffee SR, Pingault JB, Smith RG, Relton CL, Woodward G, McArdle W, Mill J, Barker ED - Mol. Psychiatry (2014)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231290&req=5

Figure 1: 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.
Mentions: We extracted probes located within the OXTR CpG island (n = 12), as this area has been previously investigated by Dadds et al (10; see Figure 1, Panel A) and others (13, 21, 22), and shown to play a key role in modulating the transcriptional activity of OXTR (23). For each probe, methylation levels were indexed by beta values (corresponding to the ratio of methylated signal divided by the sum of the methylated and unmethylated signal). Factor analysis was used to reduce the 12 OXTR probes into a smaller set of factors, which accounted for shared variance between them (24). A 3-factor solution (see Figure 1A) showed the best fit to the data as well as good temporal stability. Full details of the factor analysis procedure and results are provided as an online supplement (SI 2–5). We present findings relating specifically to Factor 2 (3 probes located on Exon 2), because (i) Factor 1 did not associate with CU at any time point in either youth with low or high internalizing problems, and (ii) Factor 3 variance was not significant at any time point, thereby precluding the examination of associations with environmental risk and CU traits.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Psychiatry, King's College London, London, UK.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus