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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.

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 (

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- to 14-year-old children from the population-based Texas Twin Project, we measured cortisol output at three different time-scales: (1) diurnal fluctuation in salivary cortisol (n = 400), (2) salivary cortisol reactivity and recovery after exposure to the Trier Social Stress Test (n = 444), and (3) and cortisol concentration in hair (n = 1,210). These measures converged on two moderately correlated, yet distinguishable, dimensions of HPA function. We then 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.

ImportanceEconomic and racial inequality is linked to disparities in children’s mental health. Biomarkers that reflect these social disparities are lacking.ObjectiveWe examined the hypothesis that salivary DNA-methylation patterns of higher inflammation and faster pace of biological aging are economically, racially and ethnically stratified and are associated with child mental health.DesignThe Texas Twin Project is an on-going, observational, longitudinal study that began in May 2012. Analyses were preregistered on May 7, 2021, and completed on August 23, 2021.SettingThe population-based study identified and recruited participants from public school rosters in the greater Austin area.ParticipantsParticipants in the analytic data set included all participants that agreed to contribute DNA samples and whose samples were assayed by January 2021.ExposuresFamily- and neighborhood-level socioeconomic inequality, racial and ethnic identities (White, Latinx, Black, Asian).Main Measure(s)Environmental exposures were analyzed in relation to salivary DNA- methylation profiles of higher inflammation (DNAm-CRP) and faster pace of biological aging (DunedinPoAm). Child internalizing problems, attention problems, aggression, rule-breaking, ADHD, oppositional defiant disorder, and conduct disorder were measured using parent-reports and self-reports on abbreviated versions of the Achenbach Child Behavior Checklist and Conners 3.The hypotheses being tested were formulated after data collection of the present data freeze and were pre-registered prior to analyses being conducted.ResultsIn a sample of N=1,183 8-to-19-year-olds (609 female, age M=13.38y), children’s salivary DNA-methylation profiles and psychiatric symptoms differed by socioeconomic conditions, race and ethnicity. Children with more parent-reported internalizing symptoms had higher DNAm-CRP (r=0.15, 95% CI=0.05 to 0.25, P=0.004) and DunedinPoAm (r=0.15, CI=0.05 to 0.25, P=0.002), and children with more parent-reported aggression problems had higher DNAm-CRP (r=0.17, CI=0.04 to 0.31, P=0.013). DNAm-CRP partially mediated advantage of higher family socioeconomic status (16% of total effect) and White racial identity (12% of total effect) on reduced internalizing symptoms. DunedinPoAm also partially mediated advantage of White racial identity on internalizing (19% of total effect).Conclusions and RelevanceSocioeconomic and racial inequality are visible in children’s epigenetic profiles of inflammation and the rate of biological aging in a manner that is tied to social disparities in mental health.Key PointsQuestionWe examined whether salivary DNA-methylation profiles are socially stratified and associated with child mental health.FindingsIn this preregistered, cross-sectional observational study of 1,183 children and adolescents, socioeconomic, racial, and ethnic disparities in mental health were associated with salivary DNA-methylation profiles of inflammation and the pace of biological aging.MeaningDNA-methylation biomarkers hold promise as tools to quantify the biological impact of socioeconomic inequality and being racially minoritized in a manner that is tied to social disparities in mental health.

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.

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 8-to 19-year-olds from the Texas Twin Project, we examined whether salivary DNA-methylation measures of inflammation (DNAm-CRP), cognitive functioning (Epigenetic-g), and pace of biological aging (DunedinPoAm) are socially stratified and associated with performance on tests of cognitive functions. We find that children growing up in more disadvantaged families and neighborhoods and children from marginalized racial/ethnic groups exhibit DNA-methylation profiles associated with higher chronic inflammation, lower cognitive functioning, and faster pace of biological aging. These salivary DNA-methylation profiles were associated with processing speed, general executive function, perceptual reasoning, verbal comprehension, reading, and math. Given that the DNA-methylation measures we examined were originally developed in adults, our results suggest that social inequalities may produce in children molecular signatures that, when observed in adults, are associated with chronic inflammation, advanced aging, and reduced cognitive function. Salivary DNA-methylation profiles might be useful as a surrogate endpoint in assessing the effectiveness of psychological and economic interventions that aim to reduce negative effects of childhood social inequality on lifespan development.Significance StatementChildren’s cognitive functioning differs by dimensions of social inequality, such as class and race. Epigenetic mechanisms that regulate gene expression might be critically involved in the biological embedding of environmental privilege and adversity. We find that children growing up in more disadvantaged families and neighborhoods and from marginalized racial/ethnic groups exhibit higher chronic inflammation, lower cognitive functioning, and a faster pace of biological aging, as indicated by novel salivary DNA-methylation measures. These DNA-methylation measures of higher inflammation, lower cognitive functioning, and a faster pace of biological aging were, in turn, associated with performance on multiple cognitive tests. DNA-methylation measures might be useful as a surrogate endpoint in evaluation of programs to address the childhood social determinants of lifelong cognitive disparities.

Genetic associations with biopsychosocial phenotypes are often interpreted as evidence that the genome codes for fixed end-states. Instead, a given genotype might regulate a dynamic range of phenotypes in response to environmental change. We collected hair cortisol (n = 1,104), salivary cortisol in reaction to an in-laboratory stressor (n = 537), and diurnal salivary cortisol (n = 488) from twins aged 8-15 years in the Texas Twin Project. Baseline genetic variation in both salivary and hair cortisol was not simply magnified after stressor exposure or after waking. Rather, novel genetic influences on cortisol arose over time. Thus, environmental change can reveal genetic variation that would not otherwise be observed in static cortisol levels. These findings are in line with the notion that the genome regulates individuals’ reactions to the environment that differ across environments.

This review examined evidence of the association between maternal pre-pregnancy overweight/obesity status and child neurodevelopmental outcomes. PubMed and PsycINFO databases were systematically searched for empirical studies published before April 2017 using keywords related to prenatal obesity and children's neurodevelopment. Of 1483 identified papers, 41 were included in the systematic review, and 32 articles representing 36 cohorts were included in the meta-analysis. Findings indicated that compared with children of normal weight mothers, children whose mothers were overweight or obese prior to pregnancy were at increased risk for compromised neurodevelopmental outcomes (overweight: OR = 1.17, 95% CI [1.11, 1.24], I2 = 65.51; obese: OR = 1.51; 95% CI [1.35, 1.69], I2 = 79.63). Pre-pregnancy obesity increased the risk of attention deficit-hyperactivity disorder (OR = 1.62; 95% CI [1.23, 2.14], I2 = 70.15), autism spectrum disorder (OR = 1.36; 95% CI [1.08, 1.70], I2 = 60.52), developmental delay (OR = 1.58; 95% CI [1.39, 1.79], I2 = 75.77) and emotional/behavioural problems (OR = 1.42; 95% CI [1.26, 1.59], I2 = 87.74). Given the current obesity prevalence among young adults and women of childbearing age, this association between maternal obesity during pregnancy and atypical child neurodevelopment represents a potentially high public health burden.

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- to 14-year-old children from the population-based Texas Twin Project, we measured cortisol output at three different time-scales: (1) diurnal fluctuation in salivary cortisol (n = 400), (2) salivary cortisol reactivity and recovery after exposure to the Trier Social Stress Test (n = 444), and (3) and cortisol concentration in hair (n = 1,210). These measures converged on two moderately correlated, yet distinguishable, dimensions of HPA function. We then 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.

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.

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.

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.