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Early life stress (ELS) is associated with lower IQ and academic achievement; however, it remains unclear whether it additionally explains their discrepancy. In 2,401 children (54% girls, 30.2% migration background) from the population-based study Generation R Study, latent factors of prenatal and postnatal (age 0-10) ELS were estimated, and IQ-achievement discrepancy (age 12) was quantified as variance in academic achievement not explained by IQ. ELS was prospectively associated with larger IQ-achievement discrepancy ([beta][subscript prenatal] = -0.24; [beta][subscript postnatal] = -0.28), lower IQ ([beta][subscript prenatal] = -0.20; [beta][subscript postnatal] = -0.22), and lower academic achievement ([beta][subscript prenatal] = -0.31; [beta][subscript postnatal] = -0.36). Associations were stronger for latent ELS than for specific ELS domains. Results point to ELS as a potential prevention target to improve academic potential.

Depression is associated with dietary factors and epigenetics. Serum cholesterol, which is prone to dietary influences, has been linked to symptoms of depression. This relationship may be (in part) due to altered epigenetic regulation of Methylenetetrahydrofolate Reductase (MTHFR). MTHFR codes for the MTHFRenzyme, which has diverse metabolic functions, and has recently been linked individually with diet, serum cholesterol levels and depressive symptoms. In 514 mother-child pairs, we examined prospective relationships between maternal (pregnancy) and child (7 years) serum cholesterol, MTHFRDNA methylation (DNAm; birth, 7 years), and development of depression symptoms from 8-15 years. After adjusting for potential confounding, we had three main findings. First, higher prenatal cholesterol associated (at a small effect size) with higher MTHFR DNAm at birth. Second, there was small effect size continuity for MTHFR DNAm between birth and age 7. Third, higher age 7 MTHFR DNAm associated with higher initial symptoms of depression symptoms at age 8, again at a small effect size. Overall, our findings provide preliminary evidence for a relationship between prenatal cholesterol, MTHFR DNAm, and symptoms of depression in children.

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. [ABSTRACT FROM AUTHOR]

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 log2 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. [ABSTRACT FROM AUTHOR]

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/m2 [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/m2) and contextual stress was independently associated with a higher BMI (0.43 kg/m2) 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Author summary: While observational research has shown a substantial degree of overlap between depression, coronary artery disease and type 2 diabetes, few studies have attempted to identify genetic variants associated with multimorbidity between these conditions. Here, we explore the shared genetic architecture of depression, coronary artery disease and type 2 diabetes (i.e., psycho-cardiometabolic diseases) and examine common genetic variants associated with the co-occurrence of these conditions. Employing a novel method for performing multivariate genome-wide association studies, we show that there are 11 independent genetic variants across nine distinct genomic risk loci associated with psycho-cardiometabolic multimorbidity. We observe enrichment in immune and inflammation-related pathways and identify 18 multimorbidity-associated genes. We show that the polygenic risk score developed based on our multimorbidity genome-wide association study is predictive of the co-occurrence of depression, coronary artery disease and type 2 diabetes in an independent sample. Lastly, we identify eight potentially causal risk factors for multimorbidity. These results advance our understanding of the shared genetic influences in psycho-cardiometabolic diseases. [ABSTRACT FROM AUTHOR]