Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children.

BACKGROUND: Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. METHODS: Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. RESULTS: Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10-07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. CONCLUSIONS: These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

Longitudinal Associations Between White Matter Microstructure and Psychiatric Symptoms in Youth.

OBJECTIVE: Associations between psychiatric problems and white matter (WM) microstructure have been reported in youth. Yet, a deeper understanding of this relation has been hampered by a dearth of well-powered longitudinal studies and a lack of explicit examination of the bidirectional associations between brain and behavior. We investigated the temporal directionality of WM microstructure and psychiatric symptom associations in youth. METHOD: In this observational study, we leveraged the world's largest single- and multi-site cohorts of neurodevelopment: the Generation R (GenR) and Adolescent Brain Cognitive Development Studies (ABCD) (total n scans = 11,400; total N = 5,700). We assessed psychiatric symptoms with the Child Behavioral Checklist as broad-band internalizing and externalizing scales, and as syndrome scales (eg, Anxious/Depressed). We quantified WM with diffusion tensor imaging (DTI), globally and at a tract level. We used cross-lagged panel models to test bidirectional associations of global and specific measures of psychopathology and WM microstructure, meta-analyzed results across cohorts, and used linear mixed-effects models for validation. RESULTS: We did not identify any longitudinal associations of global WM microstructure with internalizing or externalizing problems across cohorts (confirmatory analyses) before, and after multiple testing corrections. We observed similar findings for longitudinal associations between tract-based microstructure with internalizing and externalizing symptoms, and for global WM microstructure with specific syndromes (exploratory analyses). Some cross-sectional associations surpassed multiple testing corrections in ABCD, but not in GenR. CONCLUSION: Uni- or bi-directionality of longitudinal associations between WM and psychiatric symptoms were not robustly identified. We have proposed several explanations for these findings, including interindividual differences, the use of longitudinal approaches, and smaller effects than expected. STUDY REGISTRATION INFORMATION: Bidirectionality Brain Function and Psychiatric Symptoms; https://doi.org/10.17605/OSF.IO/PNY92.

Levels of Physical Activity at Age 10 Years and Brain Morphology Changes From Ages 10 to 14 Years.

Importance: Physical activity may promote healthy brain development in children, but previous research was predominantly cross-sectional and included small samples, providing limited knowledge. Objective: To investigate the longitudinal associations of physical activity with brain morphology changes. Design, Setting, and Participants: A 4-year longitudinal population-based cohort study in Rotterdam, the Netherlands, embedded in Generation R, a cohort from fetal life onward. From the women enrolled during pregnancy, children who had repeated measures of brain structure at ages 10 (range 8 to 12) years and 14 (range 13 to 15) years were included. Data were collected from March 2013 to November 2015 (baseline) and from October 2016 to January 2020 (follow-up). Data were analyzed from April to December 2022. Exposure: At age 10 years, both the child and their primary caregiver reported the child's levels of physical activity with regard to sport participation, outdoor play, and total physical activity. Primary analyses were based on an average multi-informant report. Main outcomes and measures: Brain morphology was quantified by magnetic resonance imaging. Hypothesized regions of interest were the bilateral amygdala and hippocampal volumes. Global brain measures were studied to test the specificity of the hypothesis. Results: Data were available for 1088 children (566 girls [52%]; 693 [64%] Dutch). Their mean (SD) age at baseline was 10.1 (0.6) years. For amygdala volume change, positive associations with multi-informant reports of total physical activity (ß = 2.6; 95% CI, 0.3-4.9) were found. Total physical activity was associated with hippocampal volume increases only when reported by the child (ß = 3.1; 95% CI, 0.4-5.8). No robust associations with global brain measures were found. Conclusions and relevance: In this cohort study of 1088 children, more physical activity at 10 years was consistently associated with an increase in amygdala volume in children aged 10 to 14 years. Physical activity and increases in hippocampal volume were found using child reports of physical activity only. These findings suggest physical activity in late childhood was prospectively associated with volumetric changes in specific subcortical structures, but not to global brain development, from late childhood to early adolescence. These findings may inform the design of future public health interventions to best facilitate neurodevelopment with physical activity.

Exploring the longitudinal associations of functional network connectivity and psychiatric symptom changes in youth.

BACKGROUND: Functional connectivity has been associated with psychiatric problems, both in children and adults, but inconsistencies are present across studies. Prior research has mostly focused on small clinical samples with cross-sectional designs. METHODS: We adopted a longitudinal design with repeated assessments to investigate associations between functional network connectivity (FNC) and psychiatric problems in youth (9- to 17-year-olds, two time points) from the general population. The largest single-site study of pediatric neurodevelopment was used: Generation R (N = 3,131 with data at either time point). Psychiatric symptoms were measured with the Child Behavioral Checklist as broadband internalizing and externalizing problems, and its eight specific syndrome scales (e.g., anxious-depressed). FNC was assessed with two complementary approaches. First, static FNC (sFNC) was measured with graph theory-based metrics. Second, dynamic FNC (dFNC), where connectivity is allowed to vary over time, was summarized into 5 states that participants spent time in. Cross-lagged panel models were used to investigate the longitudinal bidirectional relationships of sFNC with internalizing and externalizing problems. Similar cross-lagged panel models were run for dFNC. RESULTS: Small longitudinal relationships between dFNC and certain syndrome scales were observed, especially for baseline syndrome scales (i.e., rule-breaking, somatic complaints, thought problems, and attention problems) predicting connectivity changes. However, no association between any of the psychiatric problems (broadband and syndrome scales) with either measure of FNC survived correction for multiple testing. CONCLUSION: We found no or very modest evidence for longitudinal associations between psychiatric problems with dynamic and static FNC in this population-based sample. Differences in findings may stem from the population drawn, study design, developmental timing, and sample sizes.

What senior academics can do to support reproducible and open research: a short, three-step guide.

Increasingly, policies are being introduced to reward and recognise open research practices, while the adoption of such practices into research routines is being facilitated by many grassroots initiatives. However, despite this widespread endorsement and support, as well as various efforts led by early career researchers, open research is yet to be widely adopted. For open research to become the norm, initiatives should engage academics from all career stages, particularly senior academics (namely senior lecturers, readers, professors) given their routine involvement in determining the quality of research. Senior academics, however, face unique challenges in implementing policy changes and supporting grassroots initiatives. Given that-like all researchers-senior academics are motivated by self-interest, this paper lays out three feasible steps that senior academics can take to improve the quality and productivity of their research, that also serve to engender open research. These steps include changing (a) hiring criteria, (b) how scholarly outputs are credited, and (c) how we fund and publish in line with open research principles. The guidance we provide is accompanied by material for further reading.

Attention-deficit hyperactivity disorder symptoms and brain morphology: Examining confounding bias.

Background: Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with adjustments for potential confounders typically overlooked in the literature (aim 1), and for the intelligence quotient (IQ) and head motion, which are generally corrected for but play ambiguous roles (aim 2). Methods: Participants were 10-year-old children from the Adolescent Brain Cognitive Development (N = 7722) and Generation R (N = 2531) Studies. Cortical area, volume, and thickness were measured with MRI and ADHD symptoms with the Child Behavior Checklist. Surface-based cross-sectional analyses were run. Results: ADHD symptoms related to widespread cortical regions when solely adjusting for demographic factors. Additional adjustments for socioeconomic and maternal behavioral confounders (aim 1) generally attenuated associations, as cluster sizes halved and effect sizes substantially reduced. Cluster sizes further changed when including IQ and head motion (aim 2), however, we argue that adjustments might have introduced bias. Conclusions: Careful confounder selection and control can help identify more robust and specific regions of associations for ADHD symptoms, across two cohorts. We provided guidance to minimizing confounding bias in psychiatric neuroimaging. Funding: Authors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM.

Delineating the Genetic Component of Gene Expression in Major Depression.

BACKGROUND: Major depression (MD) is determined by a multitude of factors including genetic risk variants that regulate gene expression. We examined the genetic component of gene expression in MD by performing a transcriptome-wide association study (TWAS), inferring gene expression-trait relationships from genetic, transcriptomic, and phenotypic information. METHODS: Genes differentially expressed in depression were identified with the TWAS FUSION method, based on summary statistics from the largest genome-wide association analysis of MD (n = 135,458 cases, n = 344,901 controls) and gene expression levels from 21 tissue datasets (brain; blood; thyroid, adrenal, and pituitary glands). Follow-up analyses were performed to extensively characterize the identified associations: colocalization, conditional, and fine-mapping analyses together with TWAS-based pathway investigations. RESULTS: Transcriptome-wide significant differences between cases and controls were found at 94 genes, approximately half of which were novel. Of the 94 significant genes, 6 represented strong, colocalized, and potentially causal associations with depression. Such high-confidence associations include NEGR1, CTC-467M3.3, TMEM106B, LRFN5, ESR2, and PROX2. Lastly, TWAS-based enrichment analysis highlighted dysregulation of gene sets for, among others, neuronal and synaptic processes. CONCLUSIONS: This study sheds further light on the genetic component of gene expression in depression by characterizing the identified associations, unraveling novel risk genes, and determining which associations are congruent with a causal model. These findings can be used as a resource for prioritizing and designing subsequent functional studies of MD.

The role of epigenetic modifications in neurodevelopmental disorders: A systematic review.

Epigenetic processes have been suggested as key mechanisms in the etiology of neurodevelopmental disorders. This systematic review summarizes the current evidence for an association between epigenetics and Autism Spectrum Disorder (ASD) and Attention/Deficit-Hyperactivity Disorder (ADHD). Six databases were searched until the 24th of October 2017. Of the 2169 retrieved articles, 29 met our inclusion criteria. While generally associations between epigenetics and neurodevelopmental disorders were reported, only a few findings were consistent across independent analyses. Differential epigenetic markers were repeatedly identified in OR2L13, C11orf21/TSPAN32, PRRT1 and H3K27 for autism, and in VIPR2 for ADHD. Overall, evidence of an association between epigenetic modifications and ASD or ADHD should be considered preliminary and based on studies suffering from numerous caveats. We highlight the need for carefully designed investigations and for greater homogeneity and provide specific recommendations for future research. Despite the current limited understanding, the suggestive findings and rapid advances in the field hold the promise of a forthcoming elucidation of the role of epigenetic modifications in neurodevelopmental disorders.