Comorbidity between depression and cardiometabolic diseases is an emerging health concern, with childhood maltreatment as a major risk factor. These conditions are also linked to unhealthy lifestyle behaviours such as physical inactivity, smoking, and alcohol intake. However, the precise degree to which lifestyle behaviours moderate the risk between childhood maltreatment and comorbid depression and cardiometabolic disease is entirely unknown. We analysed clinical and self-reported data from four longitudinal studies (Npooled = 181,423; mean follow-up period of 5–18 years) to investigate the moderating effects of physical activity, smoking, and alcohol intake, on the association between retrospectively reported childhood maltreatment and i) depression, ii) cardiometabolic disease and iii) their comorbidity in older adults (mean age range of 47–66 years). Estimates of these moderation effects were derived using multinomial logistic regressions and then meta-analysed. No meaningful moderation effects were detected for any of the lifestyle behaviours on the association between childhood maltreatment and each health outcome. Physical activity was linked to lower odds of depression (OR [95

Background Recent work suggests that DNA methylation can be used as a proxy of fetal glucocorticoid exposure (MPS-GC), showing associations with maternal psychopathology during pregnancy. However, it is unknown whether the MPS-GC may act as a marker for broader prenatal stress and whether it partially mediates associations of prenatal stress with child internalizing and externalizing symptoms. Methods Using harmonized data from three prospective birth cohorts (Npooled = 6086), we examined whether a cumulative measure of prenatal stress, and its individual stress domains, associate with the MPS-GC in cord blood at birth. Next, we examined (i) whether the MPS-GC at birth associates with child psychiatric symptoms, (ii) whether this association is moderated by postnatal stress, and (iii) whether the effect of prenatal stress on child psychiatric symptoms is partially mediated by the MPS-GC at birth. Results Our meta-analysis revealed no significant associations between the MPS-GC at birth and prenatal stress or the individual stress domains. Moreover, the MPS-GC did not significantly associate with later child internalizing or externalizing symptoms, and there were no moderating effects of postnatal stress. Additionally, while prenatal stress significantly associated with child psychiatric symptoms, we found no partial mediation via the MPS-GC at birth. Conclusions We did not find support that the MPS-GC in cord blood reliably proxies prenatal stress, associates with child psychiatric risk, or partially mediates the associations between prenatal stress and psychiatric risk.

BACKGROUND:Depressive symptoms and cardio-metabolic risk factors often co-occur. However, our understanding of the potential mechanisms and temporal dynamics underlying their co-development remains elusive. METHODS:This population-based cohort study examined bidirectional longitudinal associations between depressive symptoms and cardio-metabolic risk factors from age 10 to 25 years, using prospective data from the ALSPAC Study. Participants with at least one (of six) follow-up measurement for each outcome were included in the analyses. We measured depressive symptoms through self- as well as parent-reports, and assessed several cardio-metabolic risk factors (including adiposity measures, lipid profiles, and inflammation). RESULTS:Among our 7,970 (47% male, 96% White) participants, we found bidirectional, within-person associations between self-reported depressive symptoms and adiposity (i.e., fat/lean mass index, but not body mass index), across the study period. Adiposity was more stable over time (β [range] = 0.75 [0.54; 0.84]), compared to depressive symptoms (0.26 [0.12; 0.38]), and it had a stronger prospective (i.e., cross-lagged) association with future depressive symptoms (0.07 [0.03, 0.13]) compared to that between depressive symptoms and future adiposity (0.04 [0.03, 0.06]). The magnitude of these associations reached its peak between 14 and 16 years. We did not find evidence of cross-lagged associations in either direction between depressive symptoms and waist circumference, insulin, triglycerides, LDL cholesterol, or C-reactive protein. CONCLUSIONS:These findings suggest a bidirectional relationship between depressive symptoms and cardio-metabolic risk factors, particularly adiposity (i.e., fat/lean mass). Adiposity showed a stronger prospective association with future depressive symptoms than vice versa; however, their relationship revealed more reciprocal than previously thought.

Abstract Background Growing evidence shows that dysregulated metabolic intrauterine environments can affect offspring’s neurodevelopment and behaviour. However, the results of individual cohort studies have been inconsistent. We aimed to investigate the association between maternal diabetes before pregnancy and gestational diabetes mellitus (GDM) with neurodevelopmental, cognitive and behavioural outcomes in children. Methods Harmonised data from > 200 000 mother-child pairs across ten birth cohorts in Europe and Australia were available. Mother-child pairs were included for analysis to determine whether GDM was recorded (yes or no) and whether at least one neurodevelopmental, cognitive and behavioural outcome was available in children aged 3 to 13 years. Confounder-adjusted regression models were used to estimate associations between maternal diabetes and child outcomes using two-stage individual participant data (IPD) meta-analysis. Model 1 included a crude estimate. The full adjustment model (model 2) included adjustment for child sex, maternal age, pre-pregnancy BMI, pregnancy weight gain, maternal smoking during pregnancy, plurality, parity and maternal education. Results Children (aged 7–10 years) born to mothers with GDM had higher attention-deficient hyperactive disorder (ADHD) symptoms compared to non-exposed controls (model 2, regression coefficient (β) 3.67 (95% CI 1.13, 6.20), P = 0.001). Moreover, children (aged 4–6 years) born to mothers with GDM exhibited more externalising problems than those born to mothers without GDM (model 2, β 2.77 (95% CI 0.52, 5.02), P = 0.01). A pre-existing maternal history of type 1 and type 2 diabetes mellitus was associated with ADHD symptoms at 4–6 years (model 1, β 8.82 (95% CI 2.21, 15.45, P = 0.009) and β 7.90 (95% CI 0.82, 14.98, P = 0.02), respectively). The association was no longer apparent in further adjustments. Conclusions This study found that children between 4 - 6 and 7–10 years of age born to mothers with GDM have a greater likelihood of developing externalising problems and ADHD symptoms, respectively. Externalising problems often co-exist with ADHD symptoms and precede formal ADHD diagnosis. Overall, this large-scale multi-cohort study suggested that a dysregulated metabolic environment during pregnancy may contribute to ADHD symptoms and externalising problems in young children.

Intrauterine stress exposure is associated with offspring health. DNA methylation (DNAm) is a putative underlying mechanism, but large population-based studies reported limited associations between prenatal stress and DNAm. Recent research has shown that environmental factors in interaction with genetic variants are better predictors of DNAm than environment or genotype alone. We investigated whether interactions of maternal prenatal stress with genetic variants are associated with DNAm at birth. We examined 2963 mother-child pairs from the population-based Generation R Study and Avon Longitudinal Study of Parents and Children, using a harmonized, comprehensive cumulative prenatal stress measure. We tested genome-wide genotype-by-prenatal stress interactions on epigenome-wide DNAm (GxEmodel), and models including only genetic variants (Gmodel) or prenatal stress (Emodel) as predictors. Follow-up analyses included Gene Ontology analyses and mediation analyses of prenatal alcohol intake, smoking, gestational age, and birth weight. We report two independent gene-by-prenatal-stress interactions on DNAm after multiple testing correction, including five genetic variants in CHD2 and ORC5, and two DNAm sites in EPPK1. By comparison, the Gmodel showed 691,202 associations and the Emodel showed three associations in genes AHRR, GFI1, and MYO1G, which could largely be explained by prenatal smoking. Genes linked to suggestive GxEmodel results were often involved in neuronal development. Our results provide some support of interaction of prenatal stress with the child’s genome on DNAm of genes related to neuronal development. Based on these models, genetic main effects on DNA methylation at birth were much more abundant than gene-by-prenatal stress interactions were.

Background Growing evidence shows that dysregulated metabolic intrauterine environments can affect neurodevelopment, cognitive and behaviour in offspring. However, results of individual cohort studies have been inconsistent. We aimed to investigate the association between maternal diabetes before pregnancy and gestational diabetes mellitus (GDM) with neurodevelopment, cognitive and behaviour outcomes in children. Methods Harmonized data from > 200 000 mother-child pairs across ten birth cohorts in Europe and Australia were available. Mother-child pairs were included for analysis to determine whether GDM was recorded (yes or no) and whether at least one neurodevelopmental, cognitive and behavioural outcome was available in children aged 3 to 13. Confounder-adjusted regression models were used to estimate associations between maternal diabetes and child outcomes using individual participant data (IPD) meta-analysis. Minimal adjustment model (model 1) included adjustments for child sex and maternal age. Full adjustment model (model 2) included adjustment for child sex and maternal age, birth weight, pre-pregnancy BMI, pregnancy weight gain, maternal smoking during pregnancy, plurality, parity, maternal education, and income. Results Children (aged 7–10 years) born to mothers with GDM had consistently higher attention-deficient hyperactive disorder (ADHD) symptoms compared to non-exposed controls (model 2, regression coefficient (β) 2.40 (95% CI 0.07, 4.73), P = 0.044)). Moreover, children (aged 4–6 years) born to mothers with GDM consistently exhibited more externalising problems than those born to mothers without GDM (model 2, β 2.50 (95% CI 0.15, 4.85), P = 0.039). In the secondary analysis, maternal history of type 1 and type 2 diabetes mellitus was associated with ADHD symptoms at 4–6 years (model 1, β 9.52 (95% CI 3.03, 16.01, P = 0.004) and β 8.73 (95% CI 1.72, 15.74, P = 0.001), respectively), the association was no longer apparent in further adjustments. Conclusions This study found that children between 4–6 and 7–10 years of age born to mothers with GDM have a greater likelihood of developing externalising problems and ADHD symptoms. Externalising problems often co-exist with ADHD symptoms and appear before medical intervention, particularly during school entry years (ages 4–6). Overall, this large-scale multi-cohort study suggested that a dysregulated metabolic environment during pregnancy may contribute to ADHD symptoms and externalising problems in young children.

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 (b [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.

Background Impaired arterial health is associated with a decline in cognitive function and psychopathology in adults. We hypothesized that these associations originate in early life. We examined the associations of blood pressure, common carotid artery intima media thickness, and carotid distensibility with behavior and cognitive outcomes during adolescence. Methods and Results This study was embedded in the Dutch Generation R Study, a population‐based prospective cohort study from early fetal life onwards. Blood pressure, carotid intima media thickness, and carotid distensibility were measured at the age of 10 years. At the age of 13 years, total, internalizing and externalizing problems and attention‐deficit hyperactivity disorder symptoms were measured using the parent‐reported Child Behavior Checklist (CBCL/6–18), autistic traits were assessed by the Social Responsiveness Scale, and IQ was assessed using the Wechsler Intelligence Scale for Children‐Fifth Edition. A 1‐SD score higher mean arterial pressure was associated with lower odds of internalizing problems (odds ratio [OR], 0.92 [95% CI, 0.85–0.99]). However, this association was nonsignificant after correction for multiple testing. Carotid intima media thickness and carotid distensibility were not associated with behavior and cognitive outcomes at 13 years old. Conclusions From our results, we cannot conclude that the associations of blood pressure, carotid intima media thickness, and carotid distensibility at age 10 years with behavior and cognitive outcomes are present in early adolescence. Further follow‐up studies are needed to identify the critical ages for arterial health in relation to behavior and cognitive outcomes at older ages.

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

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.

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).

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.

Abstract Background Although it is well‐established that both genetics and the environment influence brain development, they are typically examined separately. Here, we aimed to prospectively investigate the interactive effects of genetic variants—from a genome‐wide approach—and early life stress (ELS) on child subcortical brain structures, and their association with subsequent mental health problems. Method Primary analyses were conducted using data from the Generation R Study (N = 2257), including genotype and cumulative prenatal and postnatal ELS scores (encompassing life events, contextual risk, parental risk, interpersonal risk, direct victimisation). Neuroimaging data were collected at age 10 years, including intracranial and subcortical brain volumes (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus). Genome‐wide association and genome‐wide‐by‐environment interaction analyses (GWEIS, run separately for prenatal/postnatal ELS) were conducted for eight brain outcomes (i.e., 24 genome‐wide analyses) in the Generation R Study (discovery). Polygenic scores (PGS) using the resulting weights were calculated in an independent (target) cohort (adolescent brain cognitive development Study; N = 10,751), to validate associations with corresponding subcortical volumes and examine links to later mother‐reported internalising and externalising problems. Results One GWEIS‐prenatal stress locus was associated with caudate volume (rs139505895, mapping onto PRSS12 and NDST3) and two GWEIS‐postnatal stress loci with the accumbens (rs2397823 and rs3130008, mapping onto CUTA, SYNGAP1, and TABP). Functional annotation revealed that these genes play a role in neuronal plasticity and synaptic function, and have been implicated in neurodevelopmental phenotypes, for example, intellectual disability, autism, and schizophrenia. None of these associations survived a more stringent correction for multiple testing across all analysis sets. In the validation sample, all PGSgenotype were associated with their respective brain volumes, but no PGSGxE associated with any subcortical volume. None of the PGS associated with internalising or externalising problems. Conclusions This study lends novel suggestive insights into gene‐environment interplay on the developing brain as well as pointing to promising candidate loci for future replication and mechanistic studies.