A cross-lagged twin study of emotional symptoms, social isolation and peer victimisation from early adolescence to emerging adulthood

Background: Emotional symptoms, such as anxiety and depressive symptoms, are common during adolescence, often persist over time, and can precede the emergence of severe anxiety and depressive disorders. Studies suggest that a vicious cycle of reciprocal influences between emotional symptoms and interpersonal difficulties may explain why some adolescents suffer from persisting emotional symptoms. However, the role of different types of interpersonal difficulties, such as social isolation and peer victimisation, in these reciprocal associations is still unclear. In addition, the lack of longitudinal twin studies conducted on emotional symptoms during adolescence means that the genetic and environmental contributions to these relationships during adolescence remain unknown. Methods: Participants (N = 15,869) from the Twins Early Development Study completed self-reports of emotional symptoms, social isolation and peer victimisation at 12, 16 and 21 years old. A phenotypic cross-lagged model examined reciprocal associations between variables over time, and a genetic extension of this model examined the aetiology of the relationships between variables at each timepoint. Results: First, emotional symptoms were reciprocally and independently associated with both social isolation and peer victimisation over time, indicating that different forms of interpersonal difficulties uniquely contributed to emotional symptoms during adolescence and vice versa. Second, early peer victimisation predicted later emotional symptoms via social isolation in mid-adolescence, indicating that social isolation may constitute an intermediate pathway through which peer victimisation predicts longer-term emotional symptoms. Finally, individual differences in emotional symptoms were mostly accounted for by non-shared environmental factors at each timepoint, and both gene–environment and individual-specific environmental mechanisms were involved in the relationships between emotional symptoms and interpersonal difficulties. Conclusions: Our study highlights the necessity to intervene early in adolescence to prevent the escalation of emotional symptoms over time and to consider social isolation and peer victimisation as important risk factors for the long-term persistence of emotional symptoms.</p

Additional file 1: Figure S1. of Methylomic markers of persistent childhood asthma: a longitudinal study of asthma-discordant monozygotic twins

Flow chart describing the methodological approach used in this study. Our analyses focused on identifying differentially methylated positions (DMPs) associated with asthma in (A) all asthma-discordant MZ twins at age 10 and (B) a sub-group with persistent asthma who were discordant for asthma at age 10 and also at age 18. Using DNA previously collected at age 5, we (C) subsequently assessed longitudinal changes in DNA methylation (between ages 5 and 10) in persistent-asthma-discordant MZ twins. Finally, we (D) examined epigenetic variation at top-ranked persistent-asthma-associated DMPs in an asthma-remission group, comprising of MZ twin pairs discordant for asthma at age 10 but concordant for no asthma phenotype at 18 and concordant unaffected MZ twin pairs where neither twin had asthma at both ages 10 and 18

Additional file 2: Tables S1–S7. of Methylomic markers of persistent childhood asthma: a longitudinal study of asthma-discordant monozygotic twins

Table S1. The top-ranked DMPs (P < 0.001) in discordant MZ twin pairs at age 10. Table S2. Gene ontology enrichment analysis for age-10 asthma-associated DMPs. Table S3. The top-ranked DMPs at age 10 in persistent-asthma-discordant MZ twins (between 10 and 18 years). Table S4. Gene ontology enrichment analysis for persistent-asthma age-10 DMPs. Table S5. The top-ranked CpG sites which show changes in DNA methylation levels between 5 and 10 years of age in the asthma-discordant MZ twins. Table S6. Gene ontology enrichment analysis of longitudinal DMPs between 5 and 10 years of age. Table S7. Monozygotic twin group details

Functional outcomes among young people with trajectories of persistent childhood psychopathology

Importance: Understanding which children in the general population are at greatest risk of poor functional outcomes could improve early screening and intervention strategies. Objective: To investigate the odds of poor outcomes in emerging adulthood (ages 17 to 20 years) for children with different mental health trajectories at ages 9 to 13 years. Design, setting, and participants: Growing Up in Ireland is a longitudinal, nationally representative population-based cohort study. Data collection began in August 2007 and was repeated most recently in September 2018. All results were weighted to account for sampling bias and attrition and were adjusted for socioeconomic factors. Data analysis took place from October 2022 to April 2023. Exposure: Four latent classes captured variation in mental health in children aged 9 and 13 years, based on the parent-completed Strengths and Difficulties Questionnaire. Classes included no psychopathology, internalizing, externalizing, and high (comorbid) psychopathology. Those who remained in the same class from ages 9 to 13 years were included. Main outcomes and measures: Poor functional outcomes in emerging adulthood were measured at approximate ages 17 years (range, 16 to 18 years) and 20 years (range, 19 to 21 years). Outcomes included poor mental health, poor physical health, social isolation, heavy substance use, frequent health service use, poor subjective well-being, and adverse educational/economic outcomes. Results: Of 5141 included participants, 2618 (50.9%) were male. A total of 3726 (72.5%) were classed as having no childhood psychopathology, 1025 (19.9%) as having persistent externalizing psychopathology, 243 (4.7%) as having persistent internalizing psychopathology, and 147 (2.9%) as having persistent high psychopathology. Having any childhood psychopathology was associated with poorer functional outcomes in emerging adulthood. The internalizing group had elevated odds of most outcomes except for heavy substance use (range of odds ratios [ORs]: 1.38 [95% CI, 1.05-1.81] for frequent health service use to 3.08 [95% CI, 2.33-4.08] for poor mental health). The externalizing group had significantly elevated odds of all outcomes, albeit with relatively small effect sizes (range of ORs: 1.38 [95% CI, 1.19-1.60] for frequent health service use to 1.98 [95% CI, 1.67-2.35] for adverse educational/economic outcomes). The high psychopathology group had elevated odds of all outcomes (nonsignificantly for frequent health service use), though with wide confidence intervals (range of ORs: 1.53 [95% CI, 1.06-2.21] for poor physical health to 2.91 [95% CI, 2.05-4.12] for poor mental health). Female participants with any psychopathology had significantly higher odds of poor physical health and frequent health service use compared with male participants with any psychopathology. Conclusions and relevance: In this longitudinal cohort study, childhood psychopathology was associated with a widespread pattern of functional impairment in emerging adulthood. Findings point to the need for a wider range of preventive interventions in child and adolescent mental health services.</p

Functional outcomes among young people with trajectories of persistent childhood psychopathology

Importance: Understanding which children in the general population are at greatest risk of poor functional outcomes could improve early screening and intervention strategies. Objective: To investigate the odds of poor outcomes in emerging adulthood (ages 17 to 20 years) for children with different mental health trajectories at ages 9 to 13 years. Design, setting, and participants: Growing Up in Ireland is a longitudinal, nationally representative population-based cohort study. Data collection began in August 2007 and was repeated most recently in September 2018. All results were weighted to account for sampling bias and attrition and were adjusted for socioeconomic factors. Data analysis took place from October 2022 to April 2023. Exposure: Four latent classes captured variation in mental health in children aged 9 and 13 years, based on the parent-completed Strengths and Difficulties Questionnaire. Classes included no psychopathology, internalizing, externalizing, and high (comorbid) psychopathology. Those who remained in the same class from ages 9 to 13 years were included. Main outcomes and measures: Poor functional outcomes in emerging adulthood were measured at approximate ages 17 years (range, 16 to 18 years) and 20 years (range, 19 to 21 years). Outcomes included poor mental health, poor physical health, social isolation, heavy substance use, frequent health service use, poor subjective well-being, and adverse educational/economic outcomes. Results: Of 5141 included participants, 2618 (50.9%) were male. A total of 3726 (72.5%) were classed as having no childhood psychopathology, 1025 (19.9%) as having persistent externalizing psychopathology, 243 (4.7%) as having persistent internalizing psychopathology, and 147 (2.9%) as having persistent high psychopathology. Having any childhood psychopathology was associated with poorer functional outcomes in emerging adulthood. The internalizing group had elevated odds of most outcomes except for heavy substance use (range of odds ratios [ORs]: 1.38 [95% CI, 1.05-1.81] for frequent health service use to 3.08 [95% CI, 2.33-4.08] for poor mental health). The externalizing group had significantly elevated odds of all outcomes, albeit with relatively small effect sizes (range of ORs: 1.38 [95% CI, 1.19-1.60] for frequent health service use to 1.98 [95% CI, 1.67-2.35] for adverse educational/economic outcomes). The high psychopathology group had elevated odds of all outcomes (nonsignificantly for frequent health service use), though with wide confidence intervals (range of ORs: 1.53 [95% CI, 1.06-2.21] for poor physical health to 2.91 [95% CI, 2.05-4.12] for poor mental health). Female participants with any psychopathology had significantly higher odds of poor physical health and frequent health service use compared with male participants with any psychopathology. Conclusions and relevance: In this longitudinal cohort study, childhood psychopathology was associated with a widespread pattern of functional impairment in emerging adulthood. Findings point to the need for a wider range of preventive interventions in child and adolescent mental health services.</p

The contribution of genetic and environmental influences on DNA methylation at autosomal sites differs as a function of average DNA methylation level at that location.

<p>Shown are estimates of additive genetic effects (A), shared environmental effects (C) and non-shared (or unique) environmental effects (E) against mean DNA methylation level. The most heritable sites are characterized by intermediate levels of DNA methylation.</p

DNA methylation at sites associated with tobacco smoking is strongly influenced by additive genetic factors.

<p>Shown is a series of density plots for estimates of (<b>a</b>) additive genetic effects (A), (<b>b</b>) shared environmental effects (C) and (<b>c</b>) non-shared environmental effects (E) at 97 differentially methylated positions (DMPs) associated with smoking (green). Also shown are density plots for A, C and E at ‘background’ sites not associated with smoking (red). Shown below is a series of scatterplots showing the correlation in DNA methylation between MZ twins (x-axis) against DZ twins (y-axis) for sites associated with smoking in (<b>d</b>) all twins, (<b>e</b>) concordant non-smokers (n = 503 twin-pairs), (<b>f</b>) twins discordant for smoking status (n = 123 twin-pairs) and (<b>g</b>) concordant smokers (n = 106 twin-pairs). The shaded area on each plot indicates the heritability estimate (using Falconer’s formula) for each site.</p

The contribution of additive genetic and environmental factors to levels of DNA methylation.

<p>Shown are the results from structural equation models to estimate the mean proportion of variance in DNA methylation explained by additive genetic effects (A), shared environmental effects (C) and unshared (or unique) environmental effects (E) across Illumina 450K probes. Results are presented separately for DNA methylation sites located on the autosomes and X-chromosome, and stratified by whether they have intermediate levels of DNAm and/or are “variable”.</p

DNA methylation sites at which inter-individual variation is correlated across tissues are characterized by higher levels of heritability.

<p>(<b>a</b>) A density plot of heritability estimates for DNA methylation at sites split by the extent to which DNA methylation co-varies between whole blood and the prefrontal cortex using data from Hannon et al (2015). Heritability is significantly higher in probes where the cross-tissue covariation in DNA methylation is high (r² > 0.5, red). (<b>b-h</b>) An example of a probe (cg08449049) at which DNA methylation is strongly influenced by additive genetic effects and also co-varies between blood and multiple regions of the human brain. Shown are scatterplots of DNA methylation values at cg08449049 for (<b>b</b>) MZ (corr = 0.851) and <b>c)</b> DZ (corr = 0.364) twin pairs. Each point represents an individual twin-pair. (<b>d</b>) A boxplot of the distribution of DNA methylation levels at cg08449049 in blood and four brain regions (PFC = prefrontal cortex, EC = entorhinal cortex, STG = superior temporal gyrus, CER = cerebellum) from the same individual donors using data generated by Hannon et al (2015). (<b>e-h</b>) Scatterplots of the DNA methylation values in blood against the DNA methylation values in each of the four brain regions showing that there is significant covariation across tissues.</p