Socially Stratified Epigenetic Profiles Are Associated With Cognitive Functioning in Children and Adolescents.

Children's cognitive functioning and educational performance are socially stratified. Social inequality, including classism and racism, may operate partly via epigenetic mechanisms that modulate neurocognitive development. Following preregistered analyses of data from 1,183 participants, ages 8 to 19 years, from the Texas Twin Project, we found that children growing up in more socioeconomically disadvantaged families and neighborhoods and children from marginalized racial/ethnic groups exhibit DNA methylation profiles that, in previous studies of adults, were indicative of higher chronic inflammation, lower cognitive functioning, and a faster pace of biological aging. Furthermore, children's salivary DNA methylation profiles were associated with their performance on in-laboratory tests of cognitive and academic skills, including processing speed, general executive function, perceptual reasoning, verbal comprehension, reading, and math. Given that the DNA methylation measures that we examined were originally developed in adults, our results suggest that children show molecular signatures that reflect the early life social determinants of lifelong disparities in health and cognition.

Weak and uneven associations of home, neighborhood, and school environments with stress hormone output across multiple timescales.

The progression of lifelong trajectories of socioeconomic inequalities in health and mortality begins in childhood. Dysregulation in cortisol, a stress hormone that is the primary output of the hypothalamus-pituitary-adrenal (HPA) axis, has been hypothesized to be a mechanism for how early environmental adversity compromises health. However, despite the popularity of cortisol as a biomarker for stress and adversity, little is known about whether cortisol output differs in children being raised in socioeconomically disadvantaged environments. Here, we show that there are few differences between advantaged and disadvantaged children in their cortisol output. In 8-14-year-old children from the population-based Texas Twin Project, we measured cortisol output at three different timescales: (a) diurnal fluctuation in salivary cortisol (n = 400), (b) salivary cortisol reactivity and recovery after exposure to the Trier Social Stress Test (n = 444), and (c) cortisol concentration in hair (n = 1210). These measures converged on two moderately correlated, yet distinguishable, dimensions of HPA function. We tested differences in cortisol output across nine aspects of social disadvantage at the home (e.g., family socioeconomic status), school (e.g., average levels of academic achievement), and neighborhood (e.g., concentrated poverty). Children living in neighborhoods with higher concentrated poverty had higher diurnal cortisol output, as measured in saliva; otherwise, child cortisol output was unrelated to any other aspect of social disadvantage. Overall, we find limited support for alteration in HPA axis functioning as a general mechanism for the health consequences of socioeconomic inequality in childhood.

The relationship between executive function, processing speed, and attention-deficit hyperactivity disorder in middle childhood.

Attention-Deficit Hyperactivity Disorder (ADHD) is a heterogeneous disorder that is highly impairing. Early, accurate diagnosis maximizes long-term positive outcomes for youth with ADHD. Tests of executive functioning (EF) are potential tools for screening and differential diagnosis of ADHD subtypes. However, previous research has been inconsistent regarding the specificity and magnitude of EF deficits across ADHD subtypes. Here, we advance knowledge of the EF-ADHD relationship by using: (1) dimensional latent factor models of ADHD that captures the heterogeneity of expression, and (2) a comprehensive, reliable battery of EF tasks and modeling relationships with a general factor of EF ability. We tested 1548 children and adolescents (ages 7-15 years) from the Texas Twin Project, a population-based cohort with a diverse socioeconomic and ethnic composition. We show that EF deficits were specific to the inattention domain of ADHD. Moreover, we found that the association between EF task performance and inattention was stable across sociodemographic groups. Our results demonstrate that failures of executive control are selectively manifested as covert inattentive symptoms, such as trouble with organization, forgetfulness, and distractedness, rather than overt symptoms, such as inappropriate talkativeness and interruption. Future research, utilizing a bifactor characterization of ADHD in clinical samples, is needed to further refine understanding of the nature of cognitive deficits in ADHD across the full range of symptom variation.

The transcription factor calcium-response factor limits NMDA receptor-dependent transcription in the developing brain.

Neuronal activity sculpts brain development by inducing the transcription of genes such as brain-derived neurotrophic factor (Bdnf) that modulate the function of synapses. Sensory experience is transduced into changes in gene transcription via the activation of calcium signaling pathways downstream of both L-type voltage-gated calcium channels (L-VGCCs) and NMDA-type glutamate receptors (NMDARs). These signaling pathways converge on the regulation of transcription factors including calcium-response factor (CaRF). Although CaRF is dispensable for the transcriptional induction of Bdnf following the activation of L-VGCCs, here we show that the loss of CaRF leads to enhanced NMDAR-dependent transcription of Bdnf as well as Arc. We identify the NMDAR subunit-encoding gene Grin3a as a regulatory target of CaRF, and we show that expression of both Carf and Grin3a is depressed by the elevation of intracellular calcium, linking the function of this transcriptional regulatory pathway to neuronal activity. We find that light-dependent activation of Bdnf and Arc transcription is enhanced in the visual cortex of young CaRF knockout mice, suggesting a role for CaRF-dependent dampening of NMDAR-dependent transcription in the developing brain. Finally, we demonstrate that enhanced Bdnf expression in CaRF-lacking neurons increases inhibitory synapse formation. Taken together, these data reveal a novel role for CaRF as an upstream regulator of NMDAR-dependent gene transcription and synapse formation in the developing brain. NMDARs promote brain development by inducing the transcription of genes, including brain-derived neurotrophic factor (BDNF). We show that the transcription factor calcium-response factor (CaRF) limits NMDAR-dependent BDNF induction by regulating expression of the NMDAR subunit GluN3A. Loss of CaRF leads to enhanced BDNF-dependent GABAergic synapse formation indicating the importance of this process for brain development. Our observation that both CaRF and GluN3A are down-regulated by intracellular calcium suggests that this may be a mechanism for experience-dependent modulation of synapse formation.

Stability of DNA-Methylation Profiles of Biological Aging in Children and Adolescents.

Background and Objectives: Methylation profile scores (MPSs) index biological aging and aging-related disease in adults and are cross-sectionally associated with social determinants of health in childhood. MPSs thus provide an opportunity to trace how aging-related biology responds to environmental changes in early life. Information regarding the stability of MPSs in early life is currently lacking. Method: We use longitudinal data from children and adolescents ages 8-18 (N = 428, M age = 12.15 years) from the Texas Twin Project. Participants contributed two waves of salivary DNA-methylation data (mean lag = 3.94 years), which were used to construct four MPSs reflecting multi-system physiological decline and mortality risk (PhenoAgeAccel and GrimAgeAccel), pace of biological aging (DunedinPACE), and cognitive function (Epigenetic-g). Furthermore, we exploit variation among participants in whether they were exposed to the COVID-19 pandemic during the course of study participation, in order to test how a historical period characterized by environmental disruption might affect children's aging-related MPSs. Results: All MPSs showed moderate longitudinal stability (test-retest rs = 0.42, 0.44, 0.46, 0.51 for PhenoAgeAccel, GrimAgeAccel, and Epigenetic-g, and DunedinPACE, respectively). No differences in the stability of MPSs were apparent between those whose second assessment took place after the onset of the COVID-19 pandemic vs. those for whom both assessments took place prior to the pandemic. Conclusions: Aging-related DNA-methylation patterns are less stable in childhood than has been previously observed in adulthood. Further developmental research on the methylome is necessary to understand which environmental perturbations in childhood impact trajectories of biological aging and when children are most sensitive to those impacts.

An in-laboratory stressor reveals unique genetic variation in child cortisol output.

Dysregulation of biological stress response, as measured by cortisol output, has been a primary candidate mechanism for how social experiences become biologically embedded. Cortisol is the primary output of the hypothalamic pituitary adrenal (HPA) axis. Cortisol levels vary systematically across the day and change in response to both sudden, acute stress experiences as well as prolonged exposure to environmental stress. Using data from 8- to 15-year-old twins in the Texas Twin Project, we investigate the extent to which genetic influences are shared across different measures of cortisol output: chronic cortisol accumulations in hair (n = 1,104), diurnal variation in salivary output (n = 488), and salivary response to a standardized, acute in-laboratory stressor (n = 537). Multivariate twin models indicate that genetic factors regulating cortisol response to the in-laboratory stressor are separable from those regulating baseline cortisol levels, naturally occurring diurnal variation in cortisol, and hair cortisol levels. These findings illustrate that novel environments can reveal unique genetic variation, reordering people in terms of their observed phenotype rather than only magnifying or mitigating preexisting differences. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

An Automated Text-Messaging Platform for Enhanced Retention and Data Collection in a Longitudinal Birth Cohort: Cohort Management Platform Analysis.

BACKGROUND: Traditional methods for recruiting and maintaining contact with participants in cohort studies include print-based correspondence, which can be unidirectional, labor intensive, and slow. Leveraging technology can substantially enhance communication, maintain engagement of study participants in cohort studies, and facilitate data collection on a range of outcomes. OBJECTIVE: This paper provides an overview of the development process and design of a cohort management platform (CMP) used in the Newborn Epigenetic STudy (NEST), a large longitudinal birth cohort study. METHODS: The platform uses short message service (SMS) text messaging to facilitate interactive communication with participants; it also semiautomatically performs many recruitment and retention procedures typically completed by research assistants over the course of multiple study follow-up visits. RESULTS: Since February 2016, 302 participants have consented to enrollment in the platform and 162 have enrolled with active engagement in the system. Daily reminders are being used to help improve adherence to the study's accelerometer wear protocol. At the time of this report, 213 participants in our follow-up study who were also registered to use the CMP were eligible for the accelerometer protocol. Preliminary data show that texters (138/213, 64.8%), when compared to nontexters (75/213, 35.2%), had significantly longer average accelerometer-wearing hours (165.6 hours, SD 56.5, vs 145.3 hours, SD 58.5, P=.01) when instructed to wear the devices for 1 full week. CONCLUSIONS: This platform can serve as a model for enhancing communication and engagement with longitudinal study cohorts, especially those involved in studies assessing environmental exposures.

A Common Polymorphism in a Williams Syndrome Gene Predicts Amygdala Reactivity and Extraversion in Healthy Adults.

BACKGROUND: Williams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior. METHODS: Through an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students. RESULTS: The GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men. CONCLUSIONS: A common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety.