Associations between hypothalamic-pituitary-adrenal axis system gene variants and cortisol reactivity in preschoolers: Main effects and gene-environment interactions

Exposure to stressful events during early development has consistently been shown to produce long lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis, which may increase vulnerability to mood and anxiety disorders. Recently reported genetic association studies indicate that these disorders may be influenced, in part, by gene-environment interactions (GxE) involving polymorphisms within the corticotrophin-releasing hormone and monoaminergic system genes. However, little is known about how genetic variants and life stress work to shape children’s neuroendocrine reactivity and emerging symptoms. Therefore, the aim of this thesis is to examine main effects of candidate genes and GxE on the neuroendocrine stress response and internalizing symptoms in a community sample of 409 preschoolers. In Chapter 2 analyses show associations between variants of the CRHR1 and CRHBP genes and children’s cortisol responses to a standardized laboratory stress task. I also found evidence for GxE, where variants of the CRH system genes moderated the impact of childhood stress on early-emerging symptoms of depression and anxiety. A functional polymorphism of the catechol-O-methyltransferase (COMT) gene, the val158met, has been implicated in the etiology of stress-related mood disorders. Therefore, in Chapter 3, I examined links between the val158met polymorphism, cortisol reactivity to stress, and internalizing symptoms. I found evidence for association between the val158met genotype and cortisol reactivity to stress. Additionally, the val158met genotype moderated the link between childhood stress and emerging symptoms of anxiety. Due to the proposed role of dopamine and serotonin gene polymorphisms in research on GxE in internalizing disorders, in Chapters 4 and 5, I examined whether associations between dopaminergic and serotonin candidate gene polymorphisms and childhood cortisol reactivity and internalizing symptoms were moderated by childhood life stress. Analyses showed evidence for GxE predicting children’s symptoms. Specifically, polymorphisms of DRD2 and DAT1 genes moderated the effect of childhood stress on emerging symptoms of anxiety. With regard to serotonin pathway polymorphisms, I found associations between the serotonin transporter promoter polymorphism (5-HTTLPR) and children’s anxious symptoms. Additionally, consistent with previously reported findings, the interaction between MAOA 30bp VNTR and childhood stress predicted child anxiety symptoms. Limitations of this work include a relatively small sample size for genetic analyses, as well as the examination of a limited number of markers at each gene. Additionally, I did not correct for multiple statistical tests in some analyses due to the hypothesis-driven nature of the work. Taken together, the analyses show the complex underpinnings of individual differences in stress regulation, and highlight specific genetic vulnerabilities that influence early psychophysiological reactivity, that may in turn contribute to the development of stress-related disorders later in development

Girls\u27 internalizing symptoms and white matter tracts in Cortico-Limbic circuitry

© 2019 The Authors 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\u27 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

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\u27s 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

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\u27 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 \u3c .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

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\u27s 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. © The Author(s) 2010

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. © 2013 Wiley Periodicals, Inc

Parental depression and child cognitive vulnerability predict children\u27s 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\u27s 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\u27s 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\u27s emerging depression risk may benefit from the examination of the interactive effects of multiple sources of vulnerability across levels of analysis

The Serotonin Transporter Promoter Polymorphism and Childhood Positive and Negative Emotionality

Association studies of the serotonin transporter promoter polymorphism (5-HTTLPR) and negative emotionality (NE) are inconclusive. However, emerging evidence suggests that the association between this polymorphism and NE may be influenced by levels of another temperament trait, positive emotionality (PE). Therefore, this study examined whether the association between the 5-HTTLPR and NE was moderated by PE. A community sample of 413 three-year-old children completed a standardized battery of laboratory tasks designed to tap temperamental emotionality. Children were also genotyped for the 5-HTTLPR. No direct association between 5-HTTLPR genotype and NE was found. However, the interaction of child PE and NE predicted 5-HTTLPR genotype. Furthermore, children with a short allele who were also low in PE had significantly greater NE than children without a short allele or children with high PE. Our findings suggest that the short allele of the 5-HTTLPR is associated with NE only in the context of low PE. Inconsistent links between NE and this gene in previous research may stem from the failure to consider other temperament traits that moderate associations. © 2010 American Psychological Association

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\u27s 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\u27s sensitivity to contextual factors. Copyright © Cambridge University Press 2013

Hearing loss prevalence and years lived with disability, 1990–2019: findings from the Global Burden of Disease Study 2019

Background Hearing loss affects access to spoken language, which can affect cognition and development, and can negatively affect social wellbeing. We present updated estimates from the Global Burden of Disease (GBD) study on the prevalence of hearing loss in 2019, as well as the condition's associated disability. Methods We did systematic reviews of population-representative surveys on hearing loss prevalence from 1990 to 2019. We fitted nested meta-regression models for severity-specific prevalence, accounting for hearing aid coverage, cause, and the presence of tinnitus. We also forecasted the prevalence of hearing loss until 2050. Findings An estimated 1·57 billion (95% uncertainty interval 1·51–1·64) people globally had hearing loss in 2019, accounting for one in five people (20·3% [19·5–21·1]). Of these, 403·3 million (357·3–449·5) people had hearing loss that was moderate or higher in severity after adjusting for hearing aid use, and 430·4 million (381·7–479·6) without adjustment. The largest number of people with moderate-to-complete hearing loss resided in the Western Pacific region (127·1 million people [112·3–142·6]). Of all people with a hearing impairment, 62·1% (60·2–63·9) were older than 50 years. The Healthcare Access and Quality (HAQ) Index explained 65·8% of the variation in national age-standardised rates of years lived with disability, because countries with a low HAQ Index had higher rates of years lived with disability. By 2050, a projected 2·45 billion (2·35–2·56) people will have hearing loss, a 56·1% (47·3–65·2) increase from 2019, despite stable age-standardised prevalence. Interpretation As populations age, the number of people with hearing loss will increase. Interventions such as childhood screening, hearing aids, effective management of otitis media and meningitis, and cochlear implants have the potential to ameliorate this burden. Because the burden of moderate-to-complete hearing loss is concentrated in countries with low health-care quality and access, stronger health-care provision mechanisms are needed to reduce the burden of unaddressed hearing loss in these settings