Gestational epigenetic age and ADHD symptoms in childhood: a prospective, multi-cohort study.

Epigenetic age acceleration (EAA), defined as the difference between chronological age and epigenetically predicted age, was calculated from multiple gestational epigenetic clocks (Bohlin, EPIC overlap, and Knight) using DNA methylation levels from cord blood in three large population-based birth cohorts: the Generation R Study (The Netherlands), the Avon Longitudinal Study of Parents and Children (United Kingdom), and the Norwegian Mother, Father and Child Cohort Study (Norway). We hypothesized that a lower EAA associates prospectively with increased ADHD symptoms. We tested our hypotheses in these three cohorts and meta-analyzed the results (n = 3383). We replicated previous research on the association between gestational age (GA) and ADHD. Both clinically measured gestational age as well as epigenetic age measures at birth were negatively associated with ADHD symptoms at ages 5-7 years (clinical GA: ß = -0.04, p < 0.001, Bohlin: ß = -0.05, p = 0.01; EPIC overlap: ß = -0.05, p = 0.01; Knight: ß = -0.01, p = 0.26). Raw EAA (difference between clinical and epigenetically estimated gestational age) was positively associated with ADHD in our main model, whereas residual EAA (raw EAA corrected for clinical gestational age) was not associated with ADHD symptoms across cohorts. Overall, findings support a link between lower gestational age (either measured clinically or using epigenetic-derived estimates) and ADHD symptoms. Epigenetic age acceleration does not, however, add unique information about ADHD risk independent of clinically estimated gestational age at birth.

Different concepts of neighborhood safety and child internalizing and externalizing behaviors.

Neighborhood safety is defined inconsistently across epidemiologic studies - a conceptual problem that results in incomparable measurements, hampering the design of health interventions. Using child behavior problems (measured via the Child Behavior Checklist) as the outcome of interest, this study directly compared four measures of neighborhood safety: two of experienced safety and two of perceived safety, with each one measured at family and community levels. These included children's direct experience of harm, parental perceptions, community crime statistics, and community perceptions. In a sample of 3291 ten-year-olds from the Generation R cohort (living in municipal Rotterdam, Netherlands, 2013), all four measures were correlated (χ2 ≥ 9.2, P < 0.002 in pairwise chi-square comparisons), but ultimately identified different levels of risk for behavioral health. Direct experiences of harm, parental perceptions, and community crime statistics were all associated with increased child internalizing behaviors (ß = 3.12, ß = 2.10, and ß = 1.77, respectively), while only experiences of harm and parental perceptions were associated with increased externalizing behaviors (ß = 2.75 and ß = 1.31, respectively). These results provide novel evidence that the conceptual distinctions underlying different measures of neighborhood safety are meaningful for child mental health and should be considered in intervention design.

Attention-deficit hyperactivity disorder symptoms and brain morphology: Addressing potential selection bias with inverse probability weighting.

The goal of this study was to examine what happens to established associations between attention deficit hyperactivity disorder (ADHD) symptoms and cortical surface and thickness regions once we apply inverse probability of censoring weighting (IPCW) to address potential selection bias. Moreover, we illustrate how different factors that predict participation contribute to potential selection bias. Participants were 9- to 11-year-old children from the Generation R study (N = 2707). Cortical area and thickness were measured with magnetic resonance imaging (MRI) and ADHD symptoms with the Child Behavior Checklist. We examined how associations between ADHD symptoms and brain morphology change when we weight our sample back to either follow-up (ages 9-11), baseline (cohort at birth), or eligible (population of Rotterdam at time of recruitment). Weights were derived using IPCW or raking and missing predictors of participation used to estimate weights were imputed. Weighting analyses to baseline and eligible increased beta coefficients for the middle temporal gyrus surface area, as well as fusiform gyrus cortical thickness. Alternatively, the beta coefficient for the rostral anterior cingulate decreased. Removing one group of variables used for estimating weights resulted in the weighted regression coefficient moving closer to the unweighted regression coefficient. In addition, we found considerably different beta coefficients for most surface area regions and all thickness measures when we did not impute missing covariate data. Our findings highlight the importance of using inverse probability weighting (IPW) in the neuroimaging field, especially in the context of mental health-related research. We found that including all variables related to exposure-outcome in the IPW model and combining IPW with multiple imputations can help reduce bias. We encourage future psychiatric neuroimaging studies to define their target population, collect information on eligible but not included participants and use inverse probability of censoring weighting (IPCW) to reduce selection bias.

Prenatal exposure to non-persistent chemicals and fetal-to-childhood growth trajectories.

INTRODUCTION: Prenatal exposure to non-persistent chemicals, including organophosphate pesticides, phthalates, and bisphenols, is associated with altered fetal and childhood growth. Few studies have examined these associations using longitudinal growth trajectories or considering exposure to chemical mixtures. METHODS: Among 777 participants from the Generation R Study, we used growth mixture models to identify weight and body mass index (BMI) trajectories using weight and height measures collected from the prenatal period to age 13. We measured exposure biomarkers for organophosphate pesticides, phthalates, and bisphenols in maternal urine at three timepoints during pregnancy. Multinomial logistic regression was used to estimate associations between averaged exposure biomarker concentrations and growth trajectories. We used quantile g-computation to estimate joint associations with growth trajectories. RESULTS: Phthalic acid (OR: 1.4, 95% CI: 1.01, 1.9) and bisphenol A (BPA; OR: 1.5, 95% CI: 1.0, 2.2) were associated with higher odds of a growth trajectory characterized by smaller prenatal and larger childhood weight relative to a referent trajectory of larger prenatal and average childhood weight. Biomarkers of organophosphate pesticides, individually and jointly, were associated with lower odds of a growth trajectory characterized by average prenatal and lower childhood weight. CONCLUSIONS: Exposure to phthalates and BPA was positively associated with a weight trajectory characterized by lower prenatal and higher childhood weight, while exposure to organophosphate pesticides was negatively associated with a trajectory of average prenatal and lower childhood weight. This study is consistent with the hypothesis that non-persistent chemical exposures disrupt growth trajectories from the prenatal period through childhood.

Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life.

BACKGROUND: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively. METHODS: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. RESULTS: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. CONCLUSIONS: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play.

The biological embedding of social adversity: How adolescent housing insecurity impacts inflammation over time.

BACKGROUND & PURPOSE: Adolescent housing insecurity is a dynamic form of social adversity that impacts child health outcomes worldwide. However, the means by which adolescent housing insecurity may become biologically embedded to influence health outcomes over the life course remain unclear. Therefore, we aimed to utilize life course perspectives and advanced causal inference methods to evaluate the potential for inflammation to contribute to the biological embedding of adolescent housing insecurity. MATERIALS AND METHODS: Using prospective data from the Great Smoky Mountains Study, we investigated the relationship between adolescent housing insecurity and whole-blood spot samples assayed for C-reactive protein (CRP). Adolescent housing insecurity was created based on annual measures of frequent residential moves, reduced standard of living, forced separation from the home, and foster care. Annual measures of CRP ranged from 0.001 mg/L to 13.6 mg/L (median = 0.427 mg/L) and were log10 transformed to account for positively skewed values. We used g-estimation of structural nested mean models to estimate a series of conditional average causal effects of adolescent housing insecurity on CRP levels from ages 11 to 16 years and interpreted the results within life course frameworks of accumulation, recency, and sensitive periods. PRINCIPAL RESULTS: Of the 1,334 participants, 427 [44.3 %] were female. Based on the conditional average causal effect, one exposure to adolescent housing insecurity from ages 11 to 16 years led to a 6.4 % (95 % CI = 0.69 - 12.4) increase in later CRP levels. Exposure at 14 years of age led to a 27.9 % increase in CRP levels at age 15 (95 % CI = 6.5 - 53.5). Recent exposures to adolescent housing insecurity (<3 years) suggested stronger associations with CRP levels than distant exposures (>3 years), but limited statistical power prevented causal conclusions regarding recency effects at the risk of a Type II Error. MAJOR CONCLUSIONS: These findings highlight inflammation-as indicated by increased CRP levels-as one potential mechanism for the biological embedding of adolescent housing insecurity. The results also suggest that adolescent housing insecurity-particularly recent, repeated, and mid-adolescent exposures-may increase the risk of poor health outcomes and should be considered a key intervention target.

Prenatal exposure to common infections and newborn DNA methylation: A prospective, population-based study.

BACKGROUND: Infections during pregnancy have been robustly associated with adverse mental and physical health outcomes in offspring, yet the underlying molecular pathways remain largely unknown. Here, we examined whether exposure to common infections in utero associates with DNA methylation (DNAm) patterns at birth and whether this in turn relates to offspring health outcomes in the general population. METHODS: Using data from 2,367 children from the Dutch population-based Generation R Study, we first performed an epigenome-wide association study to identify differentially methylated sites and regions at birth associated with prenatal infection exposure. We also examined the influence of infection timing by using self-reported cumulative infection scores for each trimester. Second, we sought to develop an aggregate methylation profile score (MPS) based on cord blood DNAm as an epigenetic proxy of prenatal infection exposure and tested whether this MPS prospectively associates with offspring health outcomes, including psychiatric symptoms, BMI, and asthma at ages 13-16 years. Third, we investigated whether prenatal infection exposure associates with offspring epigenetic age acceleration - a marker of biological aging. Across all analysis steps, we tested whether our findings replicate in 864 participants from an independent population-based cohort (ALSPAC, UK). RESULTS: We observed no differentially methylated sites or regions in cord blood in relation to prenatal infection exposure, after multiple testing correction. 33 DNAm sites showed suggestive associations (p < 5e10 - 5; of which one was also nominally associated in ALSPAC), indicating potential links to genes associated with immune, neurodevelopmental, and cardiovascular pathways. While the MPS of prenatal infections associated with maternal reports of infections in the internal hold out sample in the Generation R Study (R2incremental = 0.049), it did not replicate in ALSPAC (R2incremental = 0.001), and it did not prospectively associate with offspring health outcomes in either cohort. Moreover, we observed no association between prenatal exposure to infections and epigenetic age acceleration across cohorts and clocks. CONCLUSION: In contrast to prior studies, which reported DNAm differences in offspring exposed to severe infections in utero, we do not find evidence for associations between self-reported clinically evident common infections during pregnancy and DNAm or epigenetic aging in cord blood within the general pediatric population. Future studies are needed to establish whether associations exist but are too subtle to be statistically meaningful with present sample sizes, whether they replicate in a cohort with a more similar infection score as our discovery cohort, whether they occur in different tissues than cord blood, and whether other biological pathways may be more relevant for mediating the effect of prenatal common infection exposure on downstream offspring health outcomes.

Early-life stress and the gut microbiome: A comprehensive population-based investigation.

Early-life stress (ELS) has been robustly associated with a range of poor mental and physical health outcomes. Recent studies implicate the gut microbiome in stress-related mental, cardio-metabolic and immune health problems, but research on humans is scarce and thus far often based on small, selected samples, often using retrospective reports of ELS. We examined associations between ELS and the human gut microbiome in a large, population-based study of children. ELS was measured prospectively from birth to 10 years of age in 2,004 children from the Generation R Study. We studied overall ELS, as well as unique effects of five different ELS domains, including life events, contextual risk, parental risk, interpersonal risk, and direct victimization. Stool microbiome was assessed using 16S rRNA sequencing at age 10 years and data were analyzed at multiple levels (i.e. α- and ß-diversity indices, individual genera and predicted functional pathways). In addition, we explored potential mediators of ELS-microbiome associations, including diet at age 8 and body mass index at 10 years. While no associations were observed between overall ELS (composite score of five domains) and the microbiome after multiple testing correction, contextual risk - a specific ELS domain related to socio-economic stress, including risk factors such as financial difficulties and low maternal education - was significantly associated with microbiome variability. This ELS domain was associated with lower α-diversity, with ß-diversity, and with predicted functional pathways involved, amongst others, in tryptophan biosynthesis. These associations were in part mediated by overall diet quality, a pro-inflammatory diet, fiber intake, and body mass index (BMI). These results suggest that stress related to socio-economic adversity - but not overall early life stress - is associated with a less diverse microbiome in the general population, and that this association may in part be explained by poorer diet and higher BMI. Future research is needed to test causality and to establish whether modifiable factors such as diet could be used to mitigate the negative effects of socio-economic adversity on the microbiome and related health consequences.

Prenatal exposure to common plasticizers: a longitudinal study on phthalates, brain volumetric measures, and IQ in youth.

Exposure to phthalates, used as plasticizers and solvents in consumer products, is ubiquitous. Despite growing concerns regarding their neurotoxicity, brain differences associated with gestational exposure to phthalates are understudied. We included 775 mother-child pairs from Generation R, a population-based pediatric neuroimaging study with prenatal recruitment, who had data on maternal gestational phthalate levels and T1-weighted magnetic resonance imaging in children at age 10 years. Maternal urinary concentrations of phthalate metabolites were measured at early, mid-, and late pregnancy. Child IQ was assessed at age 14 years. We investigated the extent to which prenatal exposure to phthalates is associated with brain volumetric measures and whether brain structural measures mediate the association of prenatal phthalate exposure with IQ. We found that higher maternal concentrations of monoethyl phthalate (mEP, averaged across pregnancy) were associated with smaller total gray matter volumes in offspring at age 10 years (ß per log10 increase in creatinine adjusted mEP = -10.7, 95%CI: -18.12, -3.28). Total gray matter volumes partially mediated the association between higher maternal mEP and lower child IQ (ß for mediated path =-0.31, 95%CI: -0.62, 0.01, p = 0.05, proportion mediated = 18%). An association of higher monoisobutyl phthalate (mIBP) and smaller cerebral white matter volumes was present only in girls, with cerebral white matter volumes mediating the association between higher maternal mIBP and lower IQ in girls. Our findings suggest the global impact of prenatal phthalate exposure on brain volumetric measures that extends into adolescence and underlies less optimal cognitive development.

Are some children genetically predisposed to poor sleep? A polygenic risk study in the general population.

BACKGROUND: Twin studies show moderate heritability of sleep traits: 40% for insomnia symptoms and 46% for sleep duration. Genome-wide association studies (GWAS) have identified genetic variants involved in insomnia and sleep duration in adults, but it is unknown whether these variants affect sleep during early development. We assessed whether polygenic risk scores for insomnia (PRS-I) and sleep duration (PRS-SD) affect sleep throughout early childhood to adolescence. METHODS: We included 2,458 children of European ancestry (51% girls). Insomnia-related items of the Child Behavior Checklist were reported by mothers at child's age 1.5, 3, and 6 years. At 10-15 years, the Sleep Disturbance Scale for Children and actigraphy were assessed in a subsample (N = 975). Standardized PRS-I and PRS-SD (higher scores indicate genetic susceptibility for insomnia and longer sleep duration, respectively) were computed at multiple p-value thresholds based on largest GWAS to date. RESULTS: Children with higher PRS-I had more insomnia-related sleep problems between 1.5 and 15 years (BPRS-I < 0.001 = .09, 95% CI: 0.05; 0.14). PRS-SD was not associated with mother-reported sleep problems. A higher PRS-SD was in turn associated with longer actigraphically estimated sleep duration (BPRS-SD < 5e08 = .05, 95% CI: 0.001; 0.09) and more wake after sleep onset (BPRS-SD < 0.005 = .25, 95% CI: 0.04; 0.47) at 10-15 years, but these associations did not survive multiple testing correction. CONCLUSIONS: Children who are genetically predisposed to insomnia have more insomnia-like sleep problems, whereas those who are genetically predisposed to longer sleep have longer sleep duration, but are also more awake during the night in adolescence. This indicates that polygenic risk for sleep traits, based on GWAS in adults, affects sleep already in children.

The role of lifestyle factors in the association between early-life stress and adolescent psycho-physical health: Moderation analysis in two European birth cohorts.

OBJECTIVE: Early-life stress (ELS) is an established risk factor for a host of adult mental and physical health problems, including both depression and obesity. Recent studies additionally showed that ELS was associated with an increased risk of comorbidity between mental and physical health problems, already in adolescence. Healthy lifestyle factors, including physical activity, sleep and diet have also been robustly linked to both emotional and physical wellbeing. However, it is yet unclear whether these lifestyle factors may moderate the association between ELS and psycho-physical comorbidity. METHODS: We investigated whether (a) participation in physical activity, (b) sleep duration, and (c) adherence to a Mediterranean diet, moderated the relationship between cumulative ELS exposure over the first 10 years of life and psycho-physical comorbidity at the age of 13.5 years. Analyses were conducted in 2022-2023, using data from two large adolescent samples based in the UK (ALSPAC; n = 8428) and The Netherlands (Generation R; n = 4268). RESULTS: Exposure to ELS was significantly associated with a higher risk of developing comorbidity, however this association was not modified by any of the three lifestyle factors investigated. Only physical activity was significantly associated with a reduced risk of comorbidity in one cohort (ORALSPAC [95%CI] = 0.73 [0.59;0.89]). CONCLUSIONS: In conclusion, while we found some evidence that more frequent physical activity may be associated with a reduction in psycho-physical comorbidity, we did not find evidence in support of the hypothesised moderation effects. However, more research is warranted to examine how these associations may evolve over time.

Residential ambient air pollution exposure and the development of white matter microstructure throughout adolescence.

BACKGROUND: Recent evidence suggests an association of air pollution exposure with brain development, but evidence on white matter microstructure in children is scarce. We investigated how air pollution exposure during pregnancy and childhood impacts longitudinal development of white matter microstructure throughout adolescence. METHODS: Our study population consisted of 4108 participants of Generation R, a large population-based birth cohort from Rotterdam, the Netherlands. Residential air pollution exposure to 14 air pollutants during pregnancy and childhood was estimated with land-use regression models. Diffusion tensor images were obtained around age 10 and 14, resulting in a total of 5422 useable scans (n = 3082 for wave 1 and n = 2340 for wave 2; n = 1314 for participants with data on both waves). We calculated whole-brain fractional anisotropy (FA) and mean diffusivity (MD) and performed single- and multi-pollutant analyses using mixed effects models adjusted for life-style and socioeconomic status variables. RESULTS: Higher exposure to PM2.5 during pregnancy, and PM10, PM2.5, PM2.5-10, and NOX during childhood was associated with a consistently lower whole-brain FA throughout adolescence (e.g. - 0.07 × 10-2 FA [95%CI -0.12; -0.02] per 1 standard deviation higher PM2.5 exposure during pregnancy). Higher exposure to silicon (Si) in PM2.5 and oxidative potential of PM2.5 during pregnancy, and PM2.5 during childhood was associated with an initial higher MD followed by a faster decrease in MD throughout adolescence (e.g. - 0.02 × 10-5 mm2/s MD [95%CI -0.03; -0.00] per year of age per 1 standard deviation higher Si exposure during pregnancy). Results were comparable when performing the analysis in children with complete data on the outcome for both neuroimaging assessments. CONCLUSIONS: Exposure to several pollutants was associated with a consistently lower whole-brain FA throughout adolescence. The association of few pollutants with whole-brain MD at baseline attenuated throughout adolescence. These findings suggest both persistent and age-limited associations of air pollution exposure with white matter microstructure.

Unique influences of pregnancy and anticipated parenting on cigarette smoking: results and implications of a within-person, between-pregnancy study.

Not all pregnant individuals want to become parents and "parenting intention" can also vary within individuals during different pregnancies. Nevertheless, the potential impact of parenting intention on health-related behavior during pregnancy has been heavily underexplored. In this study, we employed a within-person between pregnancy design to estimate the effect of parenting-specific influences on smoking, separate from pregnancy-specific and individual-level influences. We quantified within-mother differences in smoking during pregnancies of infants they reared (n = 84) versus pregnancies of infants they placed for adoption at birth (n = 65) using multivariate mixed-effects Poisson regression models. Mean cigarettes/day declined as the pregnancy progressed regardless of whether infants were reared or placed. However, participants smoked fewer cigarettes/day during reared pregnancies. Relative to "adopted" pregnancies, smoking during "reared" pregnancies was lower by 24%, 41%, and 54% in first (95% CI 0.64-0.90; p = 0.001), second (95% CI 0.48-0.72; p < 0.001), and third trimesters (95% CI 0.36-0.59; p < 0.001), respectively, independent of between-pregnancy differences in maternal age, fetal sex, parity, and pregnancy complications. Female sex and nulliparity were protective. Parenting intention was associated with a protective effect on pregnancy smoking independent of pregnancy-specific influences and individual characteristics. Failure to consider the impact of parenting intention on health-related behavior during pregnancy could perpetuate an unrealistic expectation to "do what's best for the baby" and stigmatize women with unintended or unwanted pregnancies.

The association of sexual minority status and bullying victimization is modified by sex and grade: findings from a nationally representative sample.

BACKGROUND: Sexual minority status is associated with face-to-face bullying and cyberbullying victimization. However, limited studies have investigated whether such a relationship differs by sex or grade in a nationally representative sample. METHODS: We concatenated the national high school data from the Youth Risk Behavior Surveillance System (YRBSS) chronologically from 2015 to 2019, resulting in a sample of 32,542 high school students. We constructed models with the interaction term between sexual minority status and biological sex assigned at birth to test the effect modification by sex on both the multiplicative and additive scales. A similar method was used to test the effect modification by grade. RESULTS: Among heterosexual students, females had a higher odds of being bullied than males, while among sexual minority students, males had a higher odds of being bullied. The effect modification by sex was significant on both the multiplicative and additive scales. We also found a decreasing trend of bullying victimization as the grade increased among both heterosexual and sexual minority students. The effect modification by the grade was significant on both the multiplicative and the additive scale. CONCLUSIONS: Teachers and public health workers should consider the difference in sex and grade when designing prevention programs to help sexual minority students.

Delaying high school start times impacts depressed mood among students: evidence from a natural experiment.

PURPOSE: Delaying high school start times prolongs weekday sleep. However, it is not clear if longer sleep reduces depression symptoms and if the impact of such policy change is the same across groups of adolescents. METHODS: We examined how gains in weekday sleep impact depression symptoms in 2,134 high school students (mean age 15.16 ± 0.35 years) from the Minneapolis metropolitan area. Leveraging a natural experiment design, we used the policy change to delay school start times as an instrument to estimate the effect of a sustained gain in weekday sleep on repeatedly measured Kandel-Davies depression symptoms. We also evaluated whether allocating the policy change to subgroups with expected benefit could improve the impact of the policy. RESULTS: Over 2 years, a sustained half-hour gain in weekday sleep expected as a result of the policy change to delay start times decreased depression symptoms by 0.78 points, 95%CI (-1.32,-0.28), or 15.6% of a standard deviation. The benefit was driven by a decrease in fatigue and sleep-related symptoms. While symptoms of low mood, hopelessness, and worry were not affected by the policy on average, older students with greater daily screen use and higher BMI experienced greater improvements in mood symptoms than would be expected on average, signaling heterogeneity. Nevertheless, universal implementation outperformed prescriptive strategies. CONCLUSION: High school start time delays are likely to universally decrease fatigue and overall depression symptoms in adolescents. Students who benefit most with respect to mood are older, spend more time on screens and have higher BMI.

Examining the interaction between prenatal stress and polygenic risk for attention-deficit/hyperactivity disorder on brain growth in childhood: Findings from the DREAM BIG consortium.

This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention-deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population-based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome-wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age-related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3-way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability.

Bidirectional associations between mental health problems and language ability across 8 years of childhood.

Research examining the development of behavior, emotions and language, and their intertwining is limited as only few studies had a longitudinal design, mostly with a short follow-up period. Moreover, most studies did not evaluate whether internalizing symptoms and externalizing symptoms are independently associated with language ability. This study examines bidirectional associations between internalizing symptoms, externalizing symptoms and language ability in childhood in a large, population-based cohort. Longitudinal data from the Millennium Cohort Study, a cohort of children in the United Kingdom followed from birth to 11 years (n = 10,878; 50.7% boys), were analyzed. Internalizing and externalizing symptoms were based on parent reports. Language ability (higher scores reflecting poorer ability) was assessed by trained interviewers at ages 3, 5, 7 and 11 years. Structural Equation Models (SEM) were performed, including random-intercept cross-lagged panel models (RI-CLPM) and cross-lagged panel models (CLPM). Internalizing symptoms, externalizing symptoms and language ability were stable over time and co-occur with each other from early life onwards. Over time, externalizing symptoms in early childhood were associated with less growth in language skills and with increases in internalizing symptoms. In late childhood, language ability was negatively associated with later internalizing and externalizing symptoms. The early start, co-occurrence and persistent nature of internalizing symptoms, externalizing symptoms and (poorer) language ability highlights the importance of comprehensive assessments in young children who present problems in one of these domains. Specifically, among children in the early grades of elementary school, those with language difficulties may benefit from careful monitoring as they are more likely to develop difficulties in behavior and emotions.

Intergenerational transmission of psychopathology across three generations: the role of social support.

Psychopathology runs in families and affects functioning of individuals and their family members. This study assessed the intergenerational transmission of psychopathology risk across three generations, and the extent to which social support factors may protect against this transmission from parents to their offspring. This study was embedded in Generation R, a multi-ethnic population-based cohort from fetal life onwards. Lifetime psychiatric disorders of grandparents were assessed with the Family Informant Schedule Criteria- updated for DSM-IV. Parental psychopathology was repeatedly measured by the Brief Symptom Inventory. Offspring psychopathology (ages 10 and 14) was assessed with the Brief Problem Monitor. Maternal and child social factors were assessed using questionnaire measures and a computerized peer nomination assessment. Our results show that the estimated additive interaction effect for the risk transmission of grandparental and pre- and postnatal parental psychopathology to offspring psychopathology was 23% (95% CI 19; 27). The joint effect of grandparental and parental psychopathology combined with maternal and child social support factors was 13% (95% CI 08; 17)], suggesting that social support factors diminished the intergenerational transmission of psychopathology from (grand)parents (G1 and G2) to offspring (G3). Transmission of psychopathology risk may have long-lasting developmental effects across generations. Social support factors reduced the vulnerability to the effects of psychopathology risk, underscoring the importance of the identification of buffering factors associated with good mental health in adolescents who are at high familial risk.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

"When I hold my daughter, she quiets, no need [for]any verbal conversation": A qualitative understanding of responsive caregiving in rural, Sindh Pakistan.

Responsive caregiving is associated with secure attachment and positive child developmental outcomes. However, there is some debate on whether responsive caregiving is a universal construct. Few studies have researched responsive caregiving in diverse cultural settings, particularly in low- and middle-income countries. In this study, we explore if and how responsive caregiving is conceptualized among mothers of children under 3-years-old in rural, Sindh Pakistan. A phenomenological qualitative study was implemented in Naushahro Feroze through in-depth interviews with twenty mothers. Mothers were asked about their aspirations for their children and how they would respond in a variety of different scenarios. Data were analyzed using thematic content analysis with an inductive-deductive coding scheme. There was substantial variation in mothers' described responsive behaviors and beliefs. Almost all mothers described using some form of responsive parenting. Responding to children's demands while the mother was preoccupied, using verbal responses to console children, and if mothers believed that children should be praised, lacked consensus. Most mothers described using breastfeeding for consolation and highlighted the importance of immediately consoling their crying child. The results suggest that there is a need for a more nuanced approach to understand caregiver behaviors across contexts.

Una sensible prestación de cuidado se asocia con una afectividad segura y con resultados positivos en el desarrollo del niño. Sin embargo, se da un debate sobre si la sensible prestación de cuidado es una estructura universal. Pocos estudios han investigado la sensible prestación de cuidado en diversos escenarios culturales, particularmente en países de bajas y medias entradas económicas. En este estudio, exploramos si la sensible prestación de cuidado está conceptualizada entre las madres de niños menores de 3 años en el área rural de Sindh en Pakistán y cómo lo está. Un estudio fenomenológico cualitativo se implementó usando datos de Naushahro Feroze (ciudad en la provincia de Sindh), por medio de entrevistas profundas con veinte madres. A las madres se les preguntó acerca de sus aspiraciones con respecto a sus niños y cómo ellas responderían en una variedad de diferentes escenarios. Se analizaron los datos usando un análisis de contenido temático con un esquema de codificación inductivo­deductivo. Hubo variación sustancial en las descripciones de las madres acerca de sus conductas y creencias sensibles. Casi todas las madres hicieron las descripciones usando alguna forma de crianza sensible. Faltó el consenso en el caso de responder a las peticiones de los niños mientras la madre estaba preocupada, en el uso de respuestas verbales para consolar a los niños, así como en el caso de si las madres creían que los niños debían ser elogiados. La mayoría de las madres hizo sus descripciones usando el amamantar como manera de consolar y subrayó la importancia de consolar inmediatamente al niño que llora. Los resultados sugieren que hay una necesidad de un acercamiento más matizado para comprender las conductas de prestación de cuidado a través de los contextos.