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This study investigated the influence of psychological factors (attitude, learning engagement, motivation, and self-efficacy) and instructional factors (teacher-related factors and learning environment) on college students' performance in higher mathematics. It developed a predictive model for higher math performance. This utilized a cross-sectional research design using a survey to gather data at a university in Cebu province, Philippines, with 391 students from Bachelor of Science in Industrial Engineering and Bachelor of Secondary Education Major in Mathematics programs selected through purposive sampling, resulting in an 87% response rate. Data were analyzed using descriptive statistics, Pearson correlation, and multiple regression. Findings revealed that students generally held positive attitudes towards math, demonstrated average learning engagement, were highly motivated, and reported average self-efficacy. Both teacher-related factors and the learning environment were perceived very positively. While both psychological and instructional factors showed significant positive correlations with mathematics performance, multiple regression analysis indicated that only attitude was not a significant predictor. Learning engagement emerged as the strongest predictor, followed by learning environment and self-efficacy. The main contribution of this study is the creation of a predictive model, Higher Mathematics Performance = 1.82 + 0.008 (attitude) + 0.257 (learning engagement) + 0.039 (motivation) + 0.098 (self-efficacy) + 0.084 (teacher-related factors) + 0.155 (learning environment) + e, which accounted for 82.7% of the variance in higher mathematics performance. Hence, the predictive model developed in this study can serve as a valuable tool to design interventions and effective strategies for improving mathematics performance and overall academic achievement in higher education. This leads to a broad picture of the fact that these factors are correlated and how the various correlations can describe strategies for proposing relevant programs necessary for the improvement of performance in higher mathematics.

The transcriptome sequencing of melanoma cells from two mouse models differing in the expression level of the scaffold protein Receptor for activated C kinase (RACK1) are presented. Primary melanoma cells were harvested from Tyr:NRasQ61K; Pax3GFP/+ mice, with or without the Tyr:Rack1-HA transgene. Cells were cultured and infected with scramble shRNA or Rack1-targeting shRNA, on technical triplicates of viral infection. Libraries were prepared by selecting polyadenylated mRNAs and RNA Sequencing (RNASeq) was performed. Samples are described in the SRA portal (SRP096162) and FASTQ files have been deposited in Sequence Read Archive (accession numbers: SRR5150106 to SRR5150117). The interpretation of these data is presented in the following research article: “RACK1 cooperates with NRASQ61K to promote melanoma in vivo” (Campagne et al., 2017, doi: 10.1016/j.cellsig.2017.03.015) [1].

Maternal immune activation (MIA) during pregnancy, as a result of infectious or inflammatory stimuli, has gained increasing attention for its potential role in adverse child neurodevelopment, with studies focusing on associations in children born preterm. This systematic review summarizes research on the link between several types of prenatal MIA and subsequent child structural and/or functional brain development outcomes. We identified 111 neuroimaging studies in five MIA areas: inflammatory biomarkers (n = 13), chorioamnionitis (n = 18), other types of infections (n = 18), human immunodeficiency virus (HIV) (n = 42), and Zika virus (n = 20). Overall, there was large heterogeneity in the type of MIA exposure examined and in study methodology. Most studies had a prospective single cohort design and mainly focused on potential effects on the brain up to one year after birth. The median sample size was 53 participants. Severe infections, i.e., HIV and Zika virus, were associated with various types of cerebral lesions (e.g., microcephaly, atrophy, or periventricular leukomalacia) that were consistently identified across studies. For less severe infections and chronic inflammation, findings were generally inconsistent and mostly included deviations in white matter structure/function. Current findings have been mainly observed in the infants' brain, presenting an opportunity for future studies to investigate whether these associations persist throughout development. Additionally, the inconsistent findings, encompassing both regions of interest and null results, call into question whether prenatal exposure to less severe infections and chronic inflammation exerts a small effect or no effect on child brain development., Competing Interests: Competing interests: The authors declare no competing financial interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth and its persistence in early childhood. Participants were from 19 pregnancy cohorts (9833 term newborns) and 6 pediatric cohorts (2429 children aged 6 to 10 years). We identified six CpGs in cord blood associated with cesarean delivery (effect size range: 0.4 to 0.7%, P < 1.0 × 10 -7 ): MAP2K2 (cg19423175), LIM2 (cg01500140), CNP (cg13917614), BLM (cg18247172), RASA3 (cg22348356), and RUNX3 (cg20674490), independent of cell proportions and other confounders. In childhood, none of these CpGs were associated with cesarean delivery, and no additional CpGs were identified. Delivery mode was associated with cell proportions at birth but not in childhood. Further research is needed to elucidate cesarean delivery's molecular influence on offspring health.

Background: Maternal immune activation (MIA) has been hypothesized to have an adverse effect on child neurodevelopment, but only a few neuroimaging studies have been performed to date, mostly in neonates. In this population-based cohort study, we investigated the association between MIA and multiple neuroimaging modalities depicting brain development from childhood to adolescence., Methods: We used data of mother-child pairs from the Generation R Study. To define our exposure, we measured interleukin (IL) 1β, IL-6, IL-17a, IL-23, interferon gamma, and C-reactive protein at 2 time points during pregnancy. Because levels of these 5 cytokines were highly correlated, we were able to compute a cytokine index. We used multiple brain imaging modalities as outcomes, including global and regional measures of brain morphology (structural magnetic resonance imaging, volume; n = 3295), white matter microstructure (diffusion magnetic resonance imaging, fractional anisotropy and mean diffusivity; n = 3267), and functional connectivity (functional magnetic resonance imaging, graph theory measures, and network-level connectivity; n = 2914) in the children at ages 10 and 14 years. We performed mixed effects models using child's age as a continuous time variable., Results: We found no significant effect of time on any neuroimaging outcomes in children over time, and there was no time × MIA interaction. These associations were similar for the cytokine index, C-reactive protein, and individual cytokines. We observed no evidence for differential effects of timing of prenatal MIA or child sex after multiple testing correction., Conclusions: In this longitudinal population-based study, we found no evidence for an association between MIA and child brain development in the general population. Our findings differ from previous research in neonates that have shown structural and functional brain abnormalities after MIA., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: DNA methylation (DNAm), an epigenetic mechanism that regulates gene activity in response to genetic and environmental influences, changes as we age. DNAm at specific sites on the genome can be used to calculate 'epigenetic clocks', which are powerful biomarkers of age, as well as of ageing. However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life. This knowledge could be used to optimise healthy ageing well before the onset of age-related conditions., Methods: We leveraged results from two longitudinal population-based cohorts (N = 5019 samples from 2348 individuals) to characterise trajectories of adult clock sites from birth to early adulthood. To explore what factors may drive early individual differences at these clock sites, we also tested for enrichment of genetic factors and prenatal exposures based on existing epigenome-wide association meta-analyses., Findings: We find that clock sites (i) diverge widely in their developmental trajectories, often showing non-linear change over time; (ii) are substantially more likely than non-clock sites to vary between individuals already from birth, differences that are predictive of DNAm variation at later ages; and (iii) show enrichment for genetic influences and prenatal environmental exposures, including prenatal smoking, diet and maternal physical health conditions., Interpretation: These results suggests that age(ing)-related epigenetic processes might originate-and differ between individuals-already very early in development. Understanding what drives these differences may in future help us to devise better strategies to promote healthy ageing., Funding: This research was conducted while C.A.M.C. was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. Full personal funding details, as well as cohort funding details, can be found in the Acknowledgements., Competing Interests: Declaration of interests The authors provide no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: DNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for - or offspring outcomes of - elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population., Methods: Our study was embedded in the prospective population-based Generation R Study (n = 2,394). We created a methylation profile score of CRP (MPS-CRP) in cord blood as a marker of neonatal inflammation and validated it against serum CRP levels in mothers during pregnancy, as well as offspring at birth and in childhood. We then examined (i) which factors (previously associated with sustained inflammation) explain variability in MPS-CRP at birth, including a wide range of prenatal lifestyle and clinical conditions, pro-inflammatory exposures, as well as child genetic liability to elevated CRP levels; and (ii) whether MPS-CRP at birth associates with child neurobehavioral outcomes, including global structural MRI and DTI measures (child mean age 10 and 14 years) as well as psychiatric symptoms over time (Child Behavioral Checklist, at mean age 1.5, 3, 6, 10 and 14 years)., Results: MPS-CRP at birth was validated with serum CRP in cord blood (cut-off > 1 mg/L) (AUC = 0.72). Prenatal lifestyle pro-inflammatory factors explained a small part (i.e., < 5%) of the variance in the MPS-CRP at birth. No other prenatal predictor or the polygenic score of CRP in the child explained significant variance in the MPS-CRP at birth. The MPS-CRP at birth prospectively associated with a reduction in global fractional anisotropy over time on mainly a nominal threshold (β = -0.014, SE = 0.007, p = 0.032), as well as showing nominal associations with structural differences (amygdala [(β = 0.016, SE = 0.006, p = 0.010], cerebellum [(β = -0.007, SE = 0.003, p = 0.036]). However, no associations with child psychiatric symptoms were observed., Conclusion: Prenatal exposure to lifestyle-related pro-inflammatory factors was the only prenatal predictor that accounted for some of the individual variability in MPS-CRP levels at birth. Further, while the MPS-CRP prospectively associated with white matter alterations over time, no associations were observed at the behavioral level. Thus, the relevance and potential utility of using epigenetic data as a marker of neonatal inflammation in the general population remain unclear. In the future, the use of epigenetic proxies for a wider range of immune markers may lend further insights into the relationship between neonatal inflammation and adverse neurodevelopment within the general pediatric population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declarations. Ethical approval: All studies included in the FAMILY framework have been approved by the respective local human research ethics committees and/or committees of animal experiments. All procedures performed in studies involving human participants are conducted in accordance with the ethical standards of the institutional and/or national research ethics committee and with the WMA Declaration of Helsinki and its latest amendments or comparable ethical standards. All animal experiments are conducted in full compliance with national/European Union directives on the protection of animals used for scientific purposes. Competing interests: BE is part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd; and has received lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, Eli Lilly Company, and Lundbeck Pharma A/S. CM has received honoraria as a consultant and/or advisor and/or for lectures from Angelini, Compass, Esteve, Exeltis Janssen, Lundbeck, Neuraxpharm, Nuvelution, Otsuka, Pfizer, Servier and Sunovion. outside the submitted work. CFB is founder and shareholder of SBGneuro Ltd. Other authors have no competing interests to declare., (© 2024. The Author(s).)

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 (R 2 incremental  = 0.049), it did not replicate in ALSPAC (R 2 incremental  = 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We aimed to determine the association of family history of dementia with structural brain measures and cognitive performance in childhood and mid-life adulthood. We studied 1,259 parents (mean age: 47.3 years, range 31.9-67.4) and 866 of their children (mean age [range] at brain MRI: 9.9 years [8.8-11.9], and for cognition: 13.5 years [12.6-15.8]) of the population-based Generation R Study. Parents filled in a questionnaire on family history, and both parents and children underwent cognitive assessment and neuroimaging. Of all participants, 109 parents (8.6%) reported a parental family history of dementia and 73 children (8.4%) had a grandparental history of dementia with mean age of dementia diagnosis in those affected 75 years (± 7.3). We observed no associations of dementia family history with cognitive ability in either parents or their children, except for worse Purdue pegboard in parents with a parental history of dementia, compared to those without (mean difference [95%CI]: -1.23 [-2.15; -0.31], test range: 21-52). In parents and children, neuroimaging measures did not differ significantly by family history. Results did not depend on age, sex, and APOE genotype. Family history of dementia was associated with worse manual dexterity in mid-life adulthood, but not with any other measures of cognitive ability or subclinical brain health in childhood and mid-life. These findings suggest that the association of family history with dementia risk is due chiefly to neurodegenerative rather than neurodevelopmental processes, and might first present with reduced motor skills., Competing Interests: Declarations. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

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: β = -0.04, p < 0.001, Bohlin: β = -0.05, p = 0.01; EPIC overlap: β = -0.05, p = 0.01; Knight: β = -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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Maternal infection during pregnancy has been identified as a prenatal risk factor for the later development of psychopathology in exposed offspring. Neuroimaging data collected during childhood has suggested a link between prenatal exposure to maternal infection and child brain structure and function, potentially offering a neurobiological explanation for the emergence of psychopathology. Additionally, preclinical studies utilizing repeated measures of neuroimaging data suggest that effects of prenatal maternal infection on the offspring's brain may normalize over time (i.e., catch-up growth). However, it remains unclear whether exposure to prenatal maternal infection in humans is related to long-term differential neurodevelopmental trajectories. Hence, this study aimed to investigate the association between prenatal exposure to infections on child brain development over time using repeated measures MRI data., Methods: We leveraged data from a population-based cohort, Generation R, in which we examined prospectively assessed self-reported infections at each trimester of pregnancy (N = 2,155). We further used three neuroimaging assessments (at mean ages 8, 10 and 14) to obtain cortical and subcortical measures of the offspring's brain morphology with MRI. Hereafter, we applied linear mixed-effects models, adjusting for several confounding factors, to estimate the association of prenatal maternal infection with child brain development over time., Results: We found that prenatal exposure to infection in the third trimester was associated with a slower decrease in volumes of the pars orbitalis, rostral anterior cingulate and superior frontal gyrus, and a faster increase in the middle temporal gyrus. In the temporal pole we observed a divergent pattern, specifically showing an increase in volume in offspring exposed to more infections compared to a decrease in volume in offspring exposed to fewer infections. We further observed associations in other frontal and temporal lobe structures after exposure to infections in any trimester, though these did not survive multiple testing correction., Conclusions: Our results suggest that prenatal exposure to infections in the third trimester may be associated with slower age-related growth in the regions: pars orbitalis, rostral anterior cingulate and superior frontal gyrus, and faster age-related growth in the middle temporal gyrus across childhood, suggesting a potential sensitive period. Our results might be interpreted as an extension of longitudinal findings from preclinical studies, indicating that children exposed to prenatal infections could exhibit catch-up growth. However, given the lack of differences in brain volume between various infection groups at baseline, there may instead be either a longitudinal deviation or a subtle temporal deviation. Subsequent well-powered studies that extend into the period of full brain development (∼25 years) are needed to confirm whether the observed phenomenon is indeed catch-up growth, a longitudinal deviation, or a subtle temporal deviation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: A large body of work has reported a link between prenatal exposure to infection and increased psychiatric risk in offspring. However, studies to date have focused primarily on exposure to severe prenatal infections and/or individual psychiatric diagnoses in clinical samples, typically measured at single time points, and without accounting for important genetic and environmental confounders. In this study, we investigated whether exposure to common infections during pregnancy is prospectively associated with repeatedly assessed child psychiatric symptoms in a large population-based study., Methods: Our study was embedded in a prospective pregnancy cohort (Generation R; n = 3,598 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. Child total, internalizing, and externalizing problems were assessed repeatedly using the parent-rated Child Behavioral Checklist (average age: 1.5, 3, 6, 10, and 14 years). Linear mixed-effects models were run adjusting for a range of confounders, including child polygenic scores for psychopathology, maternal chronic illness, birth complications, and infections during childhood. We also investigated trimester-specific effects and child sex as a potential moderator., Results: Prenatal exposure to infections was associated with higher child total, internalizing, and externalizing problems, showing temporally persistent effects, even after adjusting for important genetic and environmental confounders. We found no evidence that prenatal infections were associated with changes in child psychiatric symptoms over time. Moreover, in our trimester-specific analysis, we did not find evidence of significant timing effects of prenatal infection on child psychiatric symptoms. No interactions with child sex were identified., Conclusions: Our research adds to evidence that common prenatal infections may be a risk factor for psychiatric symptoms in children. We also extend previous findings by showing that these associations are present early on, and that rather than changing over time, they persist into adolescence. However, unmeasured confounding may still explain in part these associations. In the future, employing more advanced causal inference designs will be crucial to establishing the degree to which these effects are causal., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes., Methods: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts ( n pooled =5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years., Outcomes: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10 -8 ), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1 ), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS., Interpretation: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia., Funding: HorizonEurope; European Research Council., Competing Interests: Declarations of interest None.

Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 15 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (N pooled DNAm = 11,299; N pooled neuroimaging = 10,133; N pooled combined = 4,914). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.

Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. To translate findings from mechanistic preclinical studies to human pregnancies, studies of serum immune markers are the mainstay. The design and interpretation of human biomarker studies require additional insights in the trajectories and drivers of peripheral immune markers. The current study mapped maternal inflammatory markers (C-reactive protein (CRP), interleukin (IL)-1β, IL-6, IL-17A, IL-23, interferon- γ ) during pregnancy and investigated the impact of demographic, environmental and genetic drivers on maternal inflammatory marker levels in four multi-ethnic and socio-economically diverse population-based cohorts with more than 12,000 pregnant participants. Additionally, pregnancy inflammatory markers were compared to pre-pregnancy levels. Cytokines showed a high correlation with each other, but not with CRP. Inflammatory marker levels showed high variability between individuals, yet high concordance within an individual over time during and pre-pregnancy. Pre-pregnancy body mass index (BMI) explained more than 9.6% of the variance in CRP, but less than 1% of the variance in cytokines. The polygenic score of CRP was the best predictor of variance in CRP (>14.1%). Gestational age and previously identified inflammation drivers, including tobacco use and parity, explained less than 1% of variance in both cytokines and CRP. Our findings corroborate differential underlying regulatory mechanisms of CRP and cytokines and are suggestive of an individual inflammatory marker baseline which is, in part, genetically driven. While prior research has mainly focused on immune marker changes throughout pregnancy, our study suggests that this field could benefit from a focus on intra-individual factors, including metabolic and genetic components.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer., Competing Interests: Declaration of interests H.H. and I.C.H. received funding from Alzheimer’s Research UK and the Dunhill Medical Trust Foundation. M.A.P. reported receiving grants and personal and travel fees from Roche, Novartis, Merck, and Biogen outside the submitted work. M. Scholz receives funding from Pfizer Inc. for a project not related to this research. C.D. serves as a consultant of Novartis Pharmaceuticals. B.F. has received educational speaking fees from Medice. N.J. and P.M.T. are MPIs of a research grant from Biogen Inc. for work unrelated to the contents of this manuscript. D.J.W. received funding from the Stroke Foundation/British Heart Foundation. D.J.S. has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda, and Vistagen. H.H. received funding from MRC, Wellcome Trust, and NIHR UCLH BRC. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm, and Janssen Cilag as well as research funding from Fresenius Medical Care., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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 β-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 β-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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD)., Methods: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months), and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism-based heritability (SNP-h 2 ) and genetic correlations (r g ) and modeled underlying factor structures with multivariate models., Results: Early-life vocabulary size was modestly heritable (SNP-h 2 = 0.08-0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (r g  = 0.07), although each measure was moderately related to toddler expressive vocabulary (r g  = 0.69 and r g  = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: r g  = 0.58 and r g  = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: r g  = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (r g  = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; r g  = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (r g  = -0.74), highlighting developmental heterogeneity., Conclusions: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 (OR ALSPAC [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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

DNA methylation (DNAm) at specific sites can be used to calculate 'epigenetic clocks', which in adulthood are used as indicators of age( ing ). However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life. This knowledge could be used to optimize healthy aging well before the onset of age-related conditions. Here, we leveraged results from two longitudinal population-based cohorts ( N =5,019 samples from 2,348 individuals) to characterize trajectories of adult clock sites from birth to early adulthood. We find that clock sites (i) diverge widely in their developmental trajectories, often showing non-linear change over time; (ii) are substantially more likely than non-clock sites to vary between individuals already from birth, differences that are predictive of DNAm variation at later ages; and (iii) show enrichment for genetic and prenatal environmental exposures, supporting an early-origins perspective to epigenetic aging., Competing Interests: Competing interests The authors provide no competing interests.

Objective: Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions., Method: Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity., Results: Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (β [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity., Conclusion: We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Exposure to specific stressors has been found to associate with higher adiposity in adulthood. However, the potential overlapping effects of stress domains have been overlooked, as well as the role of parenting-related stressors that mothers are widely exposed to in mid-adulthood. Therefore, we assessed the association of overlapping effects of stress domains, including parenting-related stress, with subsequent adiposity in mothers. In 3957 mothers from the population-based Generation R Study, life stress was assessed during the first 10 years of child-rearing and measured as a reflective latent variable of stress domains. Structural equation modelling was used to assess the association of life stress and its individual domains with body mass index (BMI) and waist circumference after 14 years of follow-up. Greater life stress over the course of 10 years was associated with a higher BMI (standardized adjusted difference: 0.57 kg/m 2 [95% CI: 0.41-0.72]) and a larger waist circumference (1.15 cm [0.72-1.57]). When examining individual stress domains, we found that life events was independently associated with a higher BMI (0.16 kg/m 2 ) and contextual stress was independently associated with a higher BMI (0.43 kg/m 2 ) and larger waist circumference (1.04 cm). Parenting stress and interpersonal stress were not independently associated with adiposity at follow-up. The overlap of multiple domains of stress in mothers is associated with a higher risk of adiposity. This effect was stronger than for individual life stress domains, reiterating the need to consider overlapping effects of different life stress domains., (© 2023 The Authors. Stress and Health published by John Wiley & Sons Ltd.)

Aim: Investigating what is underlying late-life depression is becoming increasingly important with the rapidly growing elderly population. Yet, the associations between plasma biomarkers of neuroaxonal damage and late-life depression remain largely unclear. Therefore, we determined cross-sectional and longitudinal associations of neurofilament light chain (NfL) with depression in middle-aged and elderly individuals, and total tau, β-amyloid 40 and 42 for comparison., Methods: We included 3,895 participants (71.78 years [SD = 7.37], 53.4% women) from the population-based Rotterdam Study. Between 2002 and 2005, NfL, total tau, β-amyloid 40 and β-amyloid 42 were determined in blood and depressive symptoms were measured with the Center for Epidemiologic Studies Depression scale (CES-D). Incident depressive events (clinically relevant depressive symptoms, depressive syndromes, major depressive disorders) were measured prospectively with the Center for Epidemiologic Studies Depression, a clinical interview and follow-up of medical records over a median follow-up of 7.0 years (interquartile range 1.80). We used linear and Cox proportional hazard regression models., Results: Each log 2 pg./mL increase in NfL was cross-sectionally associated with more depressive symptoms (adjusted mean difference: 0.32, 95% CI 0.05-0.58), as well as with an increased risk of any incident depressive event over time (hazard ratio: 1.22, 95% CI 1.01-1.47). Further, more amyloid-β 40 was cross-sectionally associated with more depressive symptoms (adjusted mean difference: 0.70, 95% CI 0.15-1.25)., Conclusion: Higher levels of NfL are cross-sectionally associated with more depressive symptoms and a higher risk of incident depressive events longitudinally. The association was stronger for NfL compared to other plasma biomarkers, suggesting a potential role of neuroaxonal damage in developing late-life depression., (© 2023 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Arterial wall thickness and stiffness, and high blood pressure have been repeatedly associated with poorer brain health. However, previous studies largely focused on mid- or late-life stages. It is unknown whether any arterial health-related brain changes may be observable already in adolescence., Methods: We examined whether (1) carotid intima-media thickness, (2) carotid distensibility, and (3) systolic blood pressure and diastolic blood pressure, measured at the age of 10 years, were associated with brain volumes and white matter microstructure (ie, fractional anisotropy and mean diffusivity) at the age of 14 years. In addition to cross-sectional analyses, we explored associations with longitudinal change in each brain outcome from 10 to 14 years. Analyses were based on 5341 children from the Generation R Study., Results: Higher diastolic blood pressure was associated with lower total brain volume (β, -0.04 [95% CI, -0.07 to -0.01]) and gray matter volume (β, -0.04 [95% CI, -0.07 to -0.01]) at the age of 14 years, with stronger associations in higher diastolic blood pressure ranges. Similar associations emerged between systolic blood pressure and brain volumes, but these were no longer significant after adjusting for birth weight. No associations were observed between blood pressure and white matter microstructure or between carotid intima-media thickness or distensibility and brain morphology., Conclusions: Arterial blood pressure, but not intima-media thickness and distensibility, is associated with structural neuroimaging markers in early adolescence. Volumetric measures may be more sensitive to these early arterial health differences compared with microstructural properties of the white matter, but further studies are needed to confirm these results and assess potential causal mechanisms., Competing Interests: Disclosures S. Defina had full access to all the data in the study and takes responsibility for its integrity and the data analysis. Data from the Generation R Study are not publicly available as the consent given by the participants does not allow for storage of individual-level data in repositories or journals. Researchers who want to access the data set for replication should submit a request to the director of the Generation R Study (generationr@erasmusmc.nl). Data access is subject to local, national, and European rules and regulations. All scripts used in data preparation and analysis are publicly available. The other authors report no conflicts.

Background: Lateral ventricular volume (LVV) enlargement has been repeatedly linked to schizophrenia; yet, what biological factors shape LVV during early development remain unclear. DNA methylation (DNAm), an essential process for neurodevelopment that is altered in schizophrenia, is a key molecular system of interest., Methods: In this study, we conducted the first epigenome-wide association study of neonatal DNAm in cord blood with LVV in childhood (measured using T1-weighted brain scans at 10 years), based on data from a large population-based birth cohort, the Generation R Study (N = 840). Employing both probe-level and methylation profile score (MPS) approaches, we further examined whether epigenetic modifications identified at birth in cord blood are: (a) also observed cross-sectionally in childhood using peripheral blood DNAm at age of 10 years (Generation R, N = 370) and (b) prospectively associated with LVV measured in young adulthood in an all-male sample from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 114)., Results: At birth, DNAm levels at four CpGs (annotated to potassium channel tetramerization domain containing 3, KCTD3; SHH signaling and ciliogenesis regulator, SDCCAG8; glutaredoxin, GLRX) prospectively associated with childhood LVV after genome-wide correction; these genes have been implicated in brain development and psychiatric traits including schizophrenia. An MPS capturing a broader epigenetic profile of LVV - but not individual top hits - showed significant cross-sectional associations with LVV in childhood in Generation R and prospectively associated with LVV in early adulthood within ALSPAC., Conclusions: This study finds suggestive evidence that DNAm at birth prospectively associates with LVV at different life stages, albeit with small effect sizes. The prediction of MPS on LVV in a childhood sample and an independent male adult sample further underscores the stability and reproducibility of DNAm as a potential marker for LVV. Future studies with larger samples and comparable time points across development are needed to further elucidate how DNAm associates with this clinically relevant brain structure and risk for neuropsychiatric disorders, and what factors explain the identified DNAm profile of LVV at birth., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Early life adversities (ELA), including exposure to childhood maltreatment, deprivation or community violence, rarely occur in isolation. This co-occurrence poses several conceptual and methodological challenges for researchers, who must decide how best to model ELA and its association with outcomes. In this commentary, we discuss how different analytical choices come with their own - often complementary - sets of assumptions, strengths and limitations, which should be carefully considered when designing research on ELA. We then summarize work published in this issue by Sisitsky et al. (Research on Child and Adolescent Psychopathology, 2023), which serves as an important example of how different approaches can be incorporated in research in order to capture ELA as a complex phenomenon, while generating actionable results. Ultimately, such integration can enhance the quality and relevance of research, contributing to a more comprehensive understanding of ELA and its effects on health outcomes, paving the way for more targeted prevention and intervention strategies to promote children's wellbeing., (© 2023. The Author(s).)

In Wertz et al. (2019), parents' polygenic scores of educational attainment (PGS-EA) predicted parental sensitive responses to the child's needs for support, as observed in a dyadic task (i.e., observed sensitivity). We aimed to replicate and expand these findings by combining longitudinal data, child genotype data and several polygenic scores in the Generation R Study. Mother-child dyads participated in two developmental periods, toddlerhood (14 months old; n = 648) and early childhood (3-4 years old, n = 613). Higher maternal PGS-EA scores predicted higher observed sensitivity in toddlerhood (b = 0.12, 95% CI 0.03, 0.20) and early childhood (b = 0.16, 95% CI 0.08, 0.24). Child PGS-EA was significantly associated with maternal sensitivity in early childhood (b = 0.11, 95% CI 0.02, 0.21), and the effect of maternal PGS-EA was no longer significant when correcting for child PGS-EA. A latent factor of PGSs based on educational attainment, intelligence (IQ) and income showed similar results. These polygenic scores might be associated with maternal cognitive and behavioral skills that help shape parenting. Maternal PGSs predicted observed sensitivity over and above the maternal phenotypes, showing an additional role for PGSs in parenting research. In conclusion, we replicated the central finding of Wertz et al. (2019) that parental PGS-EA partially explains parental sensitivity. Our findings may be consistent with evocative gene-environment correlation (rGE), emphasizing the dynamic nature of parenting behavior across time, although further research using family trios is needed to adequately test this hypothesis., (© 2023 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Early life stress is robustly associated with poor sleep across life. Preliminary studies suggest that these associations may begin already in utero. Here, we study the longitudinal associations of prenatal psychosocial stress with sleep across childhood, and assess whether prenatal stress interacts with genetic liability for poor sleep.The study is embedded in the Generation R population-based birth cohort. Caregivers reported on prenatal psychosocial stress (life events, contextual, parental or interpersonal stressors) and on children's sleep at ages 2 months, 1.5, 2, 3 and 6 years. The study sample consisted of 4,930 children; polygenic risk scores for sleep traits were available in 2,063.Prenatal stress was consistently associated with more sleep problems across assessments. Effect sizes ranged from small (B = 0.21, 95%CI: 0.14;0.27) at 2 months to medium (B = 0.45, 95%CI: 0.38;0.53) at 2 years. Prenatal stress was moreover associated with shorter sleep duration at 2 months (B hrs  = -0.22, 95%CI: -0.32;-0.12) and at 2 years (B hrs  = -0.04, 95%CI -0.07; -0.001), but not at 3 years (B hrs  = 0.02, 95%CI: -0.02;0.06). Prenatal negative life events interacted with polygenic risk for insomnia to exacerbate sleep problems at 6 years (B interaction  = 0.07, 95%CI: 0.02;0.13).Psychosocial stress during pregnancy has negative associations with children's sleep that persist across childhood, and are exacerbated by genetic liability for insomnia. Associations with sleep duration were more pronounced in infancy and seem to attenuate with age. These findings highlight the role of the prenatal environment for developing sleep regulation, and could inform early intervention programs targeting sleep in children from high-risk pregnancies., (© 2023. The Author(s).)

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Exposure to infections during pregnancy may be a potential risk factor for later psychopathology, but large-scale epidemiological studies investigating associations between prenatal infection and long-term offspring behavioral problems in the general population are scarce. In our study, we aimed to investigate the following: (1) the association between prenatal infection and adolescent behavior, (2) putative underlying pathways (mediation), and (3) "second hits" interacting with prenatal infection to increase the risk of adolescent behavior problems (moderation)., Method: Our study was embedded in a prospective Dutch pregnancy cohort (Generation R; n = 2,213 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. At age 13 to 16 years, we assessed total, internalizing, and externalizing problems, and autistic traits using the Child Behavioral Checklist and the Social Responsiveness Scale, respectively. We investigated maternal lifestyle and nutrition, perinatal factors (placental health and delivery outcomes), and child health (lifestyle, traumatic events, infections) as mediators and moderators., Results: We observed associations of prenatal infection with adolescent total behavioral, internalizing, and externalizing problems. The association between prenatal infection and internalizing problems was moderated by higher levels of maternal psychopathology, alcohol and tobacco use, and a higher number of traumatic childhood events. We found no association between prenatal infection and autistic traits. Yet, children exposed to prenatal infections and maternal substance use, and/or traumatic childhood events, had a higher risk of autistic traits in adolescence., Conclusion: Prenatal infection may be a risk factor for later psychiatric problems as well as a disease primer making individuals susceptible to other hits later in life., Study Preregistration Information: Prenatal maternal infection and adverse neurodevelopment: a structural equation modelling approach to downstream environmental hits; https://osf.io/cp85a; cp85a., Diversity & Inclusion Statement: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.

Introduction: Little is understood about the dynamic interplay between brain morphology and cognitive ability across the life course. Additionally, most existing research has focused on global morphology measures such as estimated total intracranial volume, mean thickness, and total surface area., Methods: Mendelian randomization was used to estimate the bidirectional effects between cognitive ability, global and regional measures of cortical thickness and surface area, estimated total intracranial volume, total white matter, and the volume of subcortical structures (N=37,864). Analyses were stratified for developmental periods (childhood, early adulthood, mid-to-late adulthood; age range: 8-81 years)., Results: The earliest effects were observed in childhood and early adulthood in the frontoparietal lobes. A bidirectional relationship was identified between higher cognitive ability, larger estimated total intracranial volume (childhood, mid-to-late adulthood) and total surface area (all life stages). A thicker posterior cingulate cortex and a larger surface area in the caudal middle frontal cortex and temporal pole were associated with greater cognitive ability. Contrary, a thicker temporal pole was associated with lower cognitive ability., Discussion: Stable effects of cognitive ability on brain morphology across the life course suggests that childhood is potentially an important window for intervention., Competing Interests: Competing interests Dr Banaschewski served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire. He received conference support or speaker’s fee by Lilly, Medice, Novartis and Shire. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. Dr Poustka served in an advisory or consultancy role for Roche and Viforpharm and received speaker’s fee by Shire. She received royalties from Hogrefe, Kohlhammer and Schattauer. The present work is unrelated to the above grants and relationships.

Autism Spectrum Disorder (ASD) is a diverse neurodevelopmental condition. Gene-environmental interactions in early stages of life might alter metabolic pathways, possibly contributing to ASD pathophysiology. Metabolomics may serve as a tool to identify underlying metabolic mechanisms contributing to ASD phenotype and could help to unravel its complex etiology. In a population-based, prospective cohort study among 783 mother-child pairs, cord blood serum concentrations of amino acids, non-esterified fatty acids, phospholipids, and carnitines were obtained using liquid chromatography coupled with tandem mass spectrometry. Autistic traits were measured at the children's ages of 6 ( n = 716) and 13 ( n = 648) years using the parent-reported Social Responsiveness Scale. Lower cord blood concentrations of SM.C.39.2 and NEFA16:1/16:0 were associated with higher autistic traits among 6-year-old children, adjusted for sex and age at outcome. After more stringent adjustment for confounders, no significant associations of cord blood metabolites and autistic traits at ages 6 and 13 were detected. Differences in lipid metabolism (SM and NEFA) might be involved in ASD-related pathways and are worth further investigation.

Background: Prior studies have reported conflicting results regarding the association of prenatal maternal depression with offspring cortisol levels. We examined associations of high levels of prenatal depressive symptoms with child cortisol biomarkers., Methods: In Project Viva (n = 925, Massachusetts USA), mothers reported their depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy, cord blood glucocorticoids were measured at delivery, and child hair cortisol levels were measured in mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In the Generation R Study (n = 1644, Rotterdam, The Netherlands), mothers reported depressive symptoms using the Brief Symptom Inventory (BSI) during pregnancy, and child hair cortisol was measured at a mean (SD) age of 6.0 (0.5) years. We used cutoffs of ≥ 13 for the EPDS and > 0.75 for the BSI to indicate high levels of prenatal depressive symptoms. We used multivariable linear regression models adjusted for child sex and age (at outcome), and maternal pre-pregnancy BMI, education, social support from friends/family, pregnancy smoking status, marital status, and household income to assess associations separately in each cohort. We also meta-analyzed childhood hair cortisol results from both cohorts., Results: 8.0% and 5.1% of women respectively experienced high levels of prenatal depressive symptoms in Project Viva and the Generation R Study. We found no associations between high levels of maternal depressive symptoms during pregnancy and child cortisol biomarkers in either cohort., Conclusions: The present study does not find support for the direct link between high levels of maternal depressive symptoms and offspring cortisol levels., (© 2023. The Author(s).)

Externalizing problems are a key predictor of individual functioning in adulthood. Therefore, identifying possible risk factors for externalising problems is valuable for optimising prevention and treatment programmes. Previous research has shown that (domains of) neuropsychological functioning predict externalising problems later in life. However, the influence of callous traits, and sex as potential moderators in this relation remains unclear. The aim of this study was to examine associations between neuropsychological functioning in children (at age 8 years) and later externalising behaviour in adolescence (at age 14 years), as well as to test the role of callous traits (at age 10 years) and sex as moderating factors. The analyses were conducted using data from 661 Dutch children from the population-based Generation R Study (47.2% female). We found no association between neuropsychological functioning and later externalising behaviour. However, callous traits predicted externalising problems at age 14 years. Further, callous traits moderated the association between neuropsychological functioning and externalising behaviour, though this association dropped below the statistical significance level when adjusted for confounders. Specifically, while higher neuropsychological functioning was associated with more externalising behaviour in children with high callous traits, lower neuropsychological functioning was not associated with externalising behaviour in children with low callous traits. Although boys showed significantly higher externalising behaviours compared to girls, no moderating effect of sex was found on the association between neuropsychological functioning and externalising behaviour. These results add to a growing body of evidence supporting a distinct neurocognitive profile in children with high vs low callousness., (© 2023. The Author(s).)

Epigenetic mechanisms, such as DNA methylation (DNAm), have gained increasing attention as potential biomarkers and mechanisms underlying risk for neurodevelopmental, psychiatric and other brain-based disorders. Yet, surprisingly little is known about the extent to which DNAm is linked to individual differences in the brain itself, and how these associations may unfold across development - a time of life when many of these disorders emerge. Here, we systematically review evidence from the nascent field of Neuroimaging Epigenetics, combining structural or functional neuroimaging measures with DNAm, and the extent to which the developmental period (birth to adolescence) is represented in these studies. We identified 111 articles published between 2011-2021, out of which only a minority (21%) included samples under 18 years of age. Most studies were cross-sectional (85%), employed a candidate-gene approach (67%), and examined DNAm-brain associations in the context of health and behavioral outcomes (75%). Nearly half incorporated genetic data, and a fourth investigated environmental influences. Overall, studies support a link between peripheral DNAm and brain imaging measures, but there is little consistency in specific findings and it remains unclear whether DNAm markers present a cause, correlate or consequence of brain alterations. Overall, there is large heterogeneity in sample characteristics, peripheral tissue and brain outcome examined as well as the methods used. Sample sizes were generally low to moderate (median n all  = 98, n developmental  = 80), and attempts at replication or meta-analysis were rare. Based on the strengths and weaknesses of existing studies, we propose three recommendations on how advance the field of Neuroimaging Epigenetics. We advocate for: (1) a greater focus on developmentally oriented research (i.e. pre-birth to adolescence); (2) the analysis of large, prospective, pediatric cohorts with repeated measures of DNAm and imaging to assess directionality; and (3) collaborative, interdisciplinary science to identify robust signals, triangulate findings and enhance translational potential., (© 2023. The Author(s).)

Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (Neffective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (rg = 0.39, P = 2e-34) and weakly correlated with depression (rg = 0.13, P = 3e-6). Depression was weakly correlated with T2D (rg = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74-2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways., Competing Interests: The authors declare no competing interests., (Copyright: © 2023 Baltramonaityte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence. We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data. In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores. Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood. These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background and Hypothesis: Previous studies have shown a robust relationship between childhood adversity and subsequent psychotic symptoms. However, the role of familial risk factors underlying this relationship remains largely unclear. Here, we tested whether offspring childhood adversity and postnatal maternal psychopathology mediated the relationship between maternal childhood adversity and offspring psychotic experiences., Study Design: N = 3068 mother-offspring dyads were included. Maternal history of childhood adversity was retrospectively assessed using the Childhood Trauma Questionnaire during pregnancy. Maternal psychopathology was assessed during and after pregnancy. Twenty-four offspring childhood adversities were assessed by maternal interview when the child was 10 years old. Offspring psychotic experiences were examined using self-report at 14 years. Structural equation mediation models were conducted to explore whether maternal postnatal psychopathology and offspring childhood adversities sequentially mediated the relationship between maternal childhood adversity and offspring psychotic experiences. Analyses were adjusted for sociodemographic confounders., Study Results: Maternal history of childhood adversity was associated with offspring childhood adversities (β = 0.12, 95% CI: 0.09 to 0.16). Offspring childhood adversity mediated the association of maternal childhood adversity with offspring hallucinations (βindirect effect = 0.008, 95% CI: 0.002 to 0.014, proportion mediated = 16.3%) and delusions (βindirect effect = 0.006, 95% CI: 0.000 to 0.012, proportion mediated = 13.1%)., Conclusions: Intergenerational transmission of childhood adversity can be considered of relevance in the etiology of psychosis vulnerability and can potentially serve as a modifiable risk factor., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Childhood maltreatment is associated with depression and cardiometabolic disease in adulthood. However, the relationships with these two diseases have so far only been evaluated in different samples and with different methodology. Thus, it remains unknown how the effect sizes magnitudes for depression and cardiometabolic disease compare with each other and whether childhood maltreatment is especially associated with the co-occurrence ("comorbidity") of depression and cardiometabolic disease. This pooled analysis examined the association of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity in adulthood., Methods: We carried out an individual participant data meta-analysis on 13 international observational studies (N = 217,929). Childhood maltreatment comprised self-reports of physical, emotional, and/or sexual abuse before 18 years. Presence of depression was established with clinical interviews or validated symptom scales and presence of cardiometabolic disease with self-reported diagnoses. In included studies, binomial and multinomial logistic regressions estimated sociodemographic-adjusted associations of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. We then additionally adjusted these associations for lifestyle factors (smoking status, alcohol consumption, and physical activity). Finally, random-effects models were used to pool these estimates across studies and examined differences in associations across sex and maltreatment types., Results: Childhood maltreatment was associated with progressively higher odds of cardiometabolic disease without depression (OR [95% CI] = 1.27 [1.18; 1.37]), depression without cardiometabolic disease (OR [95% CI] = 2.68 [2.39; 3.00]), and comorbidity between both conditions (OR [95% CI] = 3.04 [2.51; 3.68]) in adulthood. Post hoc analyses showed that the association with comorbidity was stronger than with either disease alone, and the association with depression was stronger than with cardiometabolic disease. Associations remained significant after additionally adjusting for lifestyle factors, and were present in both males and females, and for all maltreatment types., Conclusions: This meta-analysis revealed that adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health. Future research should investigate the potential benefits of early intervention in individuals with a history of maltreatment on their distal mental and somatic health (PROSPERO CRD42021239288)., (© 2023. The Author(s).)

The general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N = 2178 and N = 2190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p = 8.58 × 10 -8 ). We also identified a significant differentially methylated region (DMR) at school-age (p = 1.63 × 10 -8 ), implicating the SHC Adaptor Protein 4 (SHC4) gene and the EP300-interacting inhibitor of differentiation 1 (EID1) gene that have been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder, schizophrenia, and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The link between the gut microbiome and the brain has gained increasing scientific and public interest for its potential to explain psychiatric risk. While differences in gut microbiome composition have been associated with several mental health problems, evidence to date has been largely based on animal models and human studies with modest sample sizes. In this cross-sectional study in 1,784 ten-year-old children from the multi-ethnic, population-based Generation R Study, we aimed to characterize associations of the gut microbiome with child mental health problems. Gut microbiome was assessed from stool samples using 16S rRNA sequencing. We focused on overall psychiatric symptoms as well as with specific domains of emotional and behavioral problems, assessed via the maternally rated Child Behavior Checklist. While we observed lower gut microbiome diversity in relation to higher overall and specific mental health problems, associations were not significant. Likewise, we did not identify any taxonomic feature associated with mental health problems after multiple testing correction, although suggestive findings indicated depletion of genera previously associated with psychiatric disorders, including Hungatella, Anaerotruncus and Oscillospiraceae. The identified compositional abundance differences were found to be similar across all mental health problems. Finally, we did not find significant enrichment for specific microbial functions in relation to mental health problems. In conclusion, based on the largest sample examined to date, we do not find clear evidence of associations between gut microbiome diversity, taxonomies or functions and mental health problems in the general pediatric population. In future, the use of longitudinal designs with repeated measurements of microbiome and psychiatric outcomes will be critical to identify whether and when associations between the gut microbiome and mental health emerge across development and into adulthood., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Depressive symptoms differ in severity and stability over time. Trajectories depicting these changes, particularly those with high late-life depressive symptoms, have been associated with poor brain health at old age. To better understand these associations across the lifespan, we examined depressive symptoms trajectories in relation to brain health in middle age. We included 1676 participants from the ORACLE Study, all were expecting a child at baseline (mean age 32.8, 66.6% women). Depressive symptoms were assessed at baseline, 3 years and 10 years after baseline. Brain health (global brain volume, subcortical structures volume, white matter lesions, cerebral microbleeds, cortical thickness, cortical surface area) was assessed 15 years after baseline. Using k-means clustering, four depressive symptoms trajectories were identified: low, low increasing, decreasing, and high increasing symptoms. The high increasing trajectory was associated with smaller brain volume compared to low symptoms, not surviving multiple testing correction. The low increasing trajectory was associated with more cortical thickness in a small region encompassing the right lateral occipital cortex compared to low symptoms. These findings show that longitudinal depressive symptoms trajectories are only minimally associated with brain health in middle age, suggesting that associations may only emerge later in life., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cognitive and brain reserve refer to individual differences that allow some people to better withstand brain pathology than others. Although early life stress has been recognized as a risk factor for low reserve in late life, no research yet has studied this across midlife., Objective: To examine the associations of life stress with brain and cognitive reserve in midlife., Methods: We included 1,232 middle-aged women who participated in the ORACLE Study between 2002-2006). Life stress was calculated as the shared variance of four cumulative stress domains, created from items measured between pregnancy and 10 years after childbirth. Brain reserve was defined as healthy-appearing brain volume measured with MRI; cognitive reserve as better cognitive functioning than expected based on age, education, and brain MRI measures, using structural equation modelling., Results: More life stress was associated with lower brain (standardized adjusted difference: -0.18 [95% CI 0.25,-0.12]) and cognitive reserve (-0.19 [-0.28,-0.10]). Although, effect sizes were typically smaller, cumulative stress domains were also associated with brain reserve (life events: -0.10 [-0.16,-0.04]; contextual stress: -0.13 [-0.19,-0.07]; parenting-related stress: -0.13[-0.19,-0.07]; interpersonal stress: -0.10 [-0.16,-0.04]) and cognitive reserve (life events: -0.18 [-0.25,-0.11]; contextual stress: -0.15 [-0.10,-0.02]; parenting-related stress: -0.10 [-0.18,-0.03]; interpersonal stress not significant)., Conclusion: Women who experience more life stress in midlife were found to have lower reserve. Effects were primarily driven by shared variance across cumulative stress domains, suggesting that focusing on single domains may underestimate effects. The effect of life stress on lower reserve may make women with stress more prone to neurodegenerative disease later in life than women without stress.

Background: Epigenetic processes are fast emerging as a promising molecular system in the search for both biomarkers and mechanisms underlying human health and disease risk, including psychopathology., Methods: In this review, we discuss the application of epigenetics (specifically DNA methylation) to research in child and adolescent mental health, with a focus on the use of developmentally sensitive datasets, such as prospective, population-based cohorts. We look back at lessons learned to date, highlight current developments in the field and areas of priority for future research. We also reflect on why epigenetic research on child and adolescent mental health currently lags behind other areas of epigenetic research and what we can do to overcome existing barriers., Results: To move the field forward, we advocate for the need of large-scale, harmonized, collaborative efforts that explicitly account for the time-varying nature of epigenetic and mental health data across development., Conclusion: We conclude with a perspective on what the future may hold in terms of translational applications as more robust signals emerge from epigenetic research on child and adolescent mental health., Competing Interests: Conflict Of Interest The authors have declared that they have no competing or potential conflicts of interest.