Child sex moderates the relationship between cortisol stress reactivity and symptoms over time.

BACKGROUND: Past work suggests that individual differences in stress reactivity have implications for the development of psychopathology; in particular, females' stress reactivity appears more closely tied to internalizing symptoms than males' reactivity. Conversely, males who are under-reactive to threat may be at risk for externalizing problems. However, little is known about when such differences may emerge, although this knowledge could have implications for early prevention. METHODS: Cortisol reactivity to a laboratory stressor was assessed in 409 three-year-old children (201 boys), along with parent-reported children's internalizing (anxiety and depression) and externalizing (oppositional-defiant and attention problems and hyperactivity) symptoms. Parent-reported symptoms were re-collected at child ages 5 (N = 379) and 8 (N = 364). Multilevel modelling was used to investigate whether the relationship between cortisol reactivity and symptoms differed between boys and girls over time. RESULTS: Girls with lower cortisol reactivity showed a negative association between depressive symptoms and time, while girls with higher reactivity showed no such association. No interaction between sex and cortisol reactivity was found for anxious symptoms. Boys with higher cortisol reactivity showed a negative association between symptoms and time, while boys with lower cortisol reactivity showed no such association. Time and ADHD symptoms were unrelated for boys, regardless of their cortisol reactivity. CONCLUSIONS: Findings suggest that the implications of stress reactivity indexed via cortisol vary for boys and girls, as well as for different symptom manifestations.

A genetic variant brain-derived neurotrophic factor (BDNF) polymorphism interacts with hostile parenting to predict error-related brain activity and thereby risk for internalizing disorders in children.

The error-related negativity (ERN) is a negative deflection in the event-related potential occurring when individuals make mistakes, and is increased in children with internalizing psychopathology. We recently found that harsh parenting predicts a larger ERN in children, and recent work has suggested that variation in the brain-derived neurotrophic factor (BDNF) gene may moderate the impact of early life adversity. Parents and children completed measures of parenting when children were 3 years old (N = 201); 3 years later, the ERN was measured and diagnostic interviews as well as dimensional symptom measures were completed. We found that harsh parenting predicted an increased ERN only among children with a methionine allele of the BDNF genotype, and evidence of moderated mediation: the ERN mediated the relationship between parenting and internalizing diagnoses and dimensional symptoms only if children had a methionine allele. We tested this model with externalizing disorders, and found that harsh parenting predicted externalizing outcomes, but the ERN did not mediate this association. These findings suggest that harsh parenting predicts both externalizing and internalizing outcomes in children; however, this occurs through different pathways that uniquely implicate error-related brain activity in the development of internalizing disorders.

The serotonin transporter promoter polymorphism moderates the continuity of behavioral inhibition in early childhood.

Persistently elevated behavioral inhibition (BI) in children is a marker of vulnerability to psychopathology. However, little research has considered the joint influences of caregiver and child factors that may moderate the continuity of BI in early childhood, particularly genetic variants that may serve as markers of biological plasticity, such as the serotonin transporter linked polymorphic region (5-HTTLPR). We explored this issue in 371 preschoolers and their caregivers, examining whether parent characteristics (i.e., overinvolvement or anxiety disorder) and child 5-HTTLPR influenced the continuity of BI between ages 3 and 5. Measures were observational ratings of child BI, observational and questionnaire measures of parenting, and parent interviews for anxiety disorder history, and children were genotyped for the 5-HTTLPR. Parent factors did not moderate the association between age 3 and age 5 BI; however, child BI at age 3 interacted with children's 5-HTTLPR variants to predict age 5 BI, such that children with at least one copy of the short allele exhibited less continuity of BI over time relative to children without this putative plasticity variant. Findings are consistent with previous work indicating the 5-HTTLPR short variant increases plasticity to contextual influences, thereby serving to decrease the continuity of BI in early childhood.

The Serotonin Transporter Promoter Variant, Stress, and Attentional Biases in Middle Childhood.

Although evidence suggests that 5-HTTLPR variants may shape risk for depression, the influence is likely complex, and involves effects on endophenotypes. We examined associations between 5-HTTLPR and biases in attention to affective stimuli in a sample of girls and a sample of both boys and girls. Children with at least one short (S) variant of the 5-HTTLPR polymorphism had lower positive attentional bias scores in both samples. This association was qualified by an interaction with stress in one sample, such that links between the S allele and decreased positive attentional bias was significant only when life stress was elevated. This difference in findings between the two samples was explained by sex differences in samples; the GXE interaction was significant only in boys. Findings are discussed in the context of sex differences in GXE.

Hair cortisol concentrations in higher- and lower-stress mother-daughter dyads: A pilot study of associations and moderators.

Hair cortisol concentrations (HCC) are receiving increased attention as a novel biomarker of psychophysiological responses to chronic stress, with potential relevance for psychopathology risk research. We examined the validity of HCC as a marker of psychosocial stress in mother (M(age) = 37.87 years)-daughter (M(age) = 7.62 years) dyads characterized by higher (n = 30) or lower (n = 30) maternal chronic stress. Additionally, we examined whether early care moderated similarity of HCC levels within dyads. Higher-stress mothers had significantly lower HCC compared to lower-stress mothers, consistent with other research showing that chronic stress leads to blunted HPA axis activity over time. Further, HCC in daughters were significantly and positively associated with previously assessed salivary cortisol stress reactivity. Finally, mother-daughter HCC associations were significantly moderated by negative parenting styles, such that associations became stronger as quality of parenting decreased. Findings overall indicate that HCC may be a useful marker of cortisol responses to chronic stress.

Parental depression and child cognitive vulnerability predict children's cortisol reactivity.

Risk for depression is expressed across multiple levels of analysis. For example, parental depression and cognitive vulnerability are known markers of depression risk, but no study has examined their interactive effects on children's cortisol reactivity, a likely mediator of early depression risk. We examined relations across these different levels of vulnerability using cross-sectional and longitudinal methods in two community samples of children. Children were assessed for cognitive vulnerability using self-reports (Study 1; n = 244) and tasks tapping memory and attentional bias (Study 2; n = 205), and their parents were assessed for depression history using structured clinical interviews. In both samples, children participated in standardized stress tasks and cortisol reactivity was assessed. Cross-sectionally and longitudinally, parental depression history and child cognitive vulnerability interacted to predict children's cortisol reactivity; associations between parent depression and elevated child cortisol activity were found when children also showed elevated depressotypic attributions as well as attentional and memory biases. Findings indicate that models of children's emerging depression risk may benefit from the examination of the interactive effects of multiple sources of vulnerability across levels of analysis.

The role of parenting and dopamine D4 receptor gene polymorphisms in children's inhibitory control.

Temperamental effortful control has important implications for children's development. Although genetic factors and parenting may influence effortful control, few studies have examined interplay between the two in predicting its development. The current study investigated associations between parenting and a facet of children's effortful control, inhibitory control (IC), and whether these associations were moderated by whether children had a 7-repeat variant of the DRD4 exon III VNTR. A community sample of 409 3-year-olds completed behavioural tasks to assess IC, and observational measures of parenting were also collected. Negative parenting was associated with lower child IC. The association between children's IC and positive parenting was moderated by children's DRD4 7-repeat status, such that children with at least one 7-repeat allele displayed lower IC than children without this allele when positive parenting was lower. These effects appeared to be primarily influenced by parent support and engagement. Results extend recent findings suggesting that some genetic polymorphisms may increase vulnerability to contextual influences.

Child dopamine active transporter 1 genotype and parenting: evidence for evocative gene-environment correlations.

The dopamine active transporter 1 (DAT1) gene is implicated in psychopathology risk. Although the processes by which this gene exerts its effects on risk are poorly understood, a small body of research suggests that the DAT1 gene influences early emerging negative emotionality, a marker of children's psychopathology risk. As child negative emotionality evokes negative parenting practices, the DAT1 gene may also play a role in gene-environment correlations. To test this model, children (N = 365) were genotyped for the DAT1 gene and participated in standardized parent-child interaction tasks with their primary caregiver. The DAT1 gene 9-repeat variant was associated with child negative affect expressed toward the parent during parent-child interactions, and parents of children with a 9-repeat allele exhibited more hostility and lower guidance/engagement than parents of children without a 9-repeat allele. These gene-environment associations were partially mediated by child negative affect toward the parent. The findings implicate a specific polymorphism in eliciting negative parenting, suggesting that evocative associations play a role in elevating children's risk for emotional trajectories toward psychopathology risk.

The serotonin transporter linked polymorphic region and brain-derived neurotrophic factor valine to methionine at position 66 polymorphisms and maternal history of depression: associations with cognitive vulnerability to depression in childhood.

Preliminary work indicates that cognitive vulnerability to depression may be associated with variants of the serotonin transporter promoter polymorphism (5-HTTLPR) and the valine to methionine at position 66 (val66met) polymorphism of the brain-derived neurotrophic factor (BDNF) gene; however, existing reports come from small samples. The present study sought to replicate and extend this research in a sample of 375 community-dwelling children and their parents. Following a negative mood induction, children completed a self-referent encoding task tapping memory for positive and negative self-descriptive traits. Consistent with previous work, we found that children with at least one short variant of the 5-HTTLPR had enhanced memory for negative self-descriptive traits. The BDNF val66met polymorphism had no main effect but was moderated by maternal depression, such that children with a BDNF methionine allele had a heightened memory for negative self-descriptive traits when mothers had experienced depression during children's lifetimes; in contrast, children with a methionine allele had low recall of negative traits when mothers had no depression history. The findings provide further support for the notion that the 5-HTTLPR is associated with cognitive markers of depression vulnerability and that the BDNF methionine allele moderates children's sensitivity to contextual factors.

Catechol-O-methyltransferase gene val158met polymorphism and depressive symptoms during early childhood.

Catechol-O-Methyltransferase (COMT) is a critical regulator of catecholamine levels in the brain. A functional polymorphism of the COMT gene, val158met, has been linked to internalizing symptoms (i.e., depression and anxiety) in adolescents and adults. We extended this research by investigating whether the val158met polymorphism was associated with childhood symptoms of depression and anxiety in two independent samples of young children (Ns = 476 and 409). In both samples, preschool-aged children were genotyped for the COMT val158met polymorphism. Symptoms of psychopathology were assessed via parent interviews and primary caregiver reports. In both samples, children homozygous for the val allele had higher levels of depressive symptoms compared to children with at least one copy of the met allele. Our findings extend previous research in older participants by showing links between the COMT val158met polymorphism and internalizing symptoms in early childhood.

Parenting and Child DRD4 Genotype Interact to Predict Children's Early Emerging Effortful Control.

Effortful control (EC), or the trait-like capacity to regulate dominant responses, has important implications for children's development. Although genetic factors and parenting likely influence EC, few studies have examined whether they interact to predict its development. This study examined whether the DRD4 exon III variable number tandem repeat polymorphism moderated the relation between parenting and children's EC. Three hundred and eighty-two 3-year-olds and primary caregivers completed behavioral tasks assessing children's EC and parenting. Children's DRD4 genotypes moderated the relation between parenting and EC: Children with at least one 7-repeat allele displayed lower EC in the context of negative parenting than children without this allele. These findings suggest opportunities for modifying early risk for low EC.

The role of brain-derived neurotrophic factor genotype, parental depression, and relationship discord in predicting early-emerging negative emotionality.

The brain-derived neurotrophic factor (BDNF) gene is a plausible candidate for early-emerging negative emotionality (NE), and evidence suggests that the effects of this gene may be especially salient in the context of familial risk for child maladjustment. We therefore examined whether the single-nucleotide polymorphism producing a valine-to-methionine substitution at codon 66 (val66met) of the BDNF gene was associated with childhood NE, in the context of parental depression and relationship discord. A sample of 413 three-year-old children was assessed for NE using standardized laboratory measures. The children's parents completed clinical interviews as well as a measure of marital satisfaction. Children with at least one BDNF methionine (met) allele exhibited elevated NE when a parent had a history of depressive disorder or when relationship discord was reported by a parent. In contrast, this allele was associated with especially low NE when parental depression was absent and when the parental relationship was not discordant. Our findings suggest that the BDNF met allele confers increased child sensitivity to both positive and negative familial influences.

Girls' internalizing symptoms and white matter tracts in Cortico-Limbic circuitry.

Dysfunction in cortico-limbic circuitry is implicated in internalizing disorders (i.e., depressive and anxious disorders), but less is known about whether structural variations precede frank disorder and thus potentially mark risk. We therefore examined associations between white matter (WM) tract microstructure in cortico-limbic circuitry at age 7 and concurrent and longitudinal patterns of internalizing symptoms in 42 typically developing girls using Diffusion Tensor Imaging (DTI). Girls' internalizing symptoms were concurrently associated with reduced fractional anisotropy (FA) in segments of the cingulum bundle (CB) and the uncinate fasciculus (UF), bilaterally. Moreover, latent profile analysis showed that girls with increasing internalizing symptoms, based on assessments at ages 3, 6, 7, and 8, had reduced FA in these segments compared to girls with stably low symptoms. These results point to a putative neural mechanism underlying the course of childhood internalizing symptoms.

An examination of the association between the 5-HTT promoter region polymorphism and depressogenic attributional styles in childhood.

Although a vast literature examining the role of attributional styles in depression has accumulated, the origins of such cognitions remain poorly understood. Investigators are increasingly interested in whether cognitive vulnerability to depression is linked to genetic variation. As a preliminary test of this hypothesis, we examined whether the serotonin transporter promoter polymorphism (5-HTTLPR) was associated with attributional styles in children. Thirty-eight children completed a self-report measure of attributional styles, the Child Attributional Style Questionnaire-Revised (CASQ-R). Children were also genotyped for the 5-HTTLPR polymorphism, including the single nucleotide polymorphism (SNP) rs25531 in the long allele of the 5-HTTLPR. The short alleles of the 5-HTTLPR and their putative functional equivalents were associated with increased levels of depressogenic attributions for negative events, as measured by the CASQ-R, lending support to the role of 5-HTTLPR polymorphisms in cognitive vulnerability to depression.

The BDNF gene val66met polymorphism and behavioral inhibition in early childhood.

Stably elevated behavioural inhibition (BI) is an established risk factor for internalizing disorders. This stability may be related to genetic factors, including a valine-to-methionine substitution on codon 66 (val66met) of the brain-derived neurotrophic factor (BDNF) gene. Past work on the BDNF met variant has inconsistently linked it to vulnerability to internalizing problems; some of this inconsistency may stem from the failure to consider gene-trait interactions in shaping the course of early BI. Toward elucidating early pathways to anxiety vulnerability, we examined gene-by-trait interactions in predicting the course of BI over time in 476 children, assessed for BI using standardized laboratory methods. We found that children with the met allele showed lower stability of BI between ages 3 and 6 than those without this allele. While the mechanisms that underlie this effect are unclear, our findings are consistent with the notion that the met variant, in the context of early BI, influences the stability of this trait in early development.

Catechol-O-Methyltransferase gene (val158met) polymorphisms and anxious symptoms in early childhood: The roles of hypothalamus-pituitary-adrenal axis reactivity and life stress.

Individual differences in hypothalamus-pituitary-adrenal (HPA) axis reactivity to stress (measured via salivary cortisol) have been widely implicated in the etiology of internalizing problems such as depression and anxiety. Literature suggests that stress during early childhood is an important source of contextual risk although its effects may be moderated by polymorphisms of neurotransmitter genes. The COMT val158met is one such polymorphism, and literature documents its link to internalizing problems. To extend these findings, and to better understand the role of this polymorphism in developmental risk, we investigated links between the val158met polymorphism and early-age cortisol response. Additionally, we investigated whether cortisol reactivity mediated the link between COMT and emerging internalizing symptoms. The study was conducted in a community sample of 409 preschoolers. Saliva samples were collected pre-stress task (baseline) and every 10min post-stress task for one-hour to asses cortisol response. Child anxious and depressive symptoms were tabulated based on parent-reports. Markers of early childhood stress included marital discord, socio-economic status and the UCLA Life Stress Interview. Findings indicated that the val158met polymorphism is associated with childhood cortisol response (p<0.05). A gene-environment interaction between val158met and life stress also predicted child anxiety symptoms (p<0.01). Finally, cortisol response mediated the main-effect of val158met on child anxiety symptoms (pathway ps<0.05). Analyses suggest that COMT val158met moderates the influence of early life stress on preschool-age symptoms of anxiety. Additionally, cortisol reactivity acts as a mechanistic mediator of the main-effect of COMT genotype on child anxious symptoms.

Gene-environment correlations in the cross-generational transmission of parenting: Grandparenting moderates the effect of child 5-HTTLPR genotype on mothers' parenting.

Evidence suggests that parenting is associated cross-generationally and that children's genes may elicit specific parenting styles (evocative gene-environment correlation). This study examined whether the effect of children's genotype, specifically 5-HTTLPR, on mothers' parenting behaviors was moderated by her own parenting experiences from her mother. Two independent samples of three-year-olds (N = 476 and 405) were genotyped for the serotonin transporter gene, and observational measures of parenting were collected. Mothers completed measures of the parenting they received as children. The child having a short allele on 5-HTTLPR was associated with more maternal hostility (sample 1 and 2) and with less maternal support (sample 1), but only if the mother reported lower quality grandmothers' parenting (abuse and indifference in Sample 1 and lower levels of grandmother care in Sample 2). Results support the possibility of a moderated evocative gene-environment correlation.

Links between white matter microstructure and cortisol reactivity to stress in early childhood: evidence for moderation by parenting.

Activity of the hypothalamic-pituitary-adrenal axis (measured via cortisol reactivity) may be a biological marker of risk for depression and anxiety, possibly even early in development. However, the structural neural correlates of early cortisol reactivity are not well known, although these would potentially inform broader models of mechanisms of risk, especially if the early environment further shapes these relationships. Therefore, we examined links between white matter architecture and young girls' cortisol reactivity and whether early caregiving moderated these links. We recruited 45 6-year-old girls based on whether they had previously shown high or low cortisol reactivity to a stress task at age 3. White matter integrity was assessed by calculating fractional anisotropy (FA) of diffusion-weighted magnetic resonance imaging scans. Parenting styles were measured via a standardized parent-child interaction task. Significant associations were found between FA in white matter regions adjacent to the left thalamus, the right anterior cingulate cortex, and the right superior frontal gyrus (all ps < .001). Further, positive early caregiving moderated the effect of high cortisol reactivity on white matter FA (all ps ≤ .05), with high stress reactive girls who received greater parent positive affect showing white matter structure more similar to that of low stress reactive girls. Results show associations between white matter integrity of various limbic regions of the brain and early cortisol reactivity to stress and provide preliminary support for the notion that parenting may moderate associations.

Child temperament and parental depression predict cortisol reactivity to stress in middle childhood.

Children's cortisol reactivity to stress is an important mediator of depression risk, making the search for predictors of such reactivity an important goal for psychopathologists. Multiple studies have linked maternal depression and childhood behavioral inhibition (BI) independently to child cortisol reactivity, yet few have tested multivariate models of these risks. Further, paternal depression and other child temperament traits, such as positive emotionality (PE), have been largely ignored despite their potential relevance. We therefore examined longitudinal associations between child fear/BI and PE and parental depression, and children's cortisol stress reactivity, in 205 7-year-olds. Paternal depression and child fear/BI predicted greater cortisol stress reactivity at a follow-up of 164 9-year-olds, and maternal depression and child PE interacted to predict children's cortisol reactivity, such that higher child PE predicted lower cortisol reactivity in the context of maternal depression. Results highlight the importance of both parents' depression, as well as multiple facets of child temperament, in developing more comprehensive models of childhood cortisol reactivity to stress.

HPA axis reactivity in early childhood: associations with symptoms and moderation by sex.

Sex differences in rates of internalizing disorders have been attributed in part to heightened sensitivity to stress in females. While the sex difference in disorder rates becomes most pronounced in adolescence, developmental research suggests that stress reactivity in girls may be related to elevated internalizing symptoms even in childhood. We therefore examined whether child sex moderated associations between symptoms of psychopathology and cortisol reactivity to a standardized stress task in 409 three-year-old community-dwelling children. Anxious symptoms were associated with elevated cortisol reactivity, but only in girls. Externalizing symptoms were unrelated to baseline cortisol or cortisol reactivity, and no evidence for moderation by child sex was found. Results suggest that cortisol reactivity to stress in early childhood has a sex-specific association with girls' internalizing symptoms.