Examining the associations between microglia genetic capacity, early life exposures and white matter development at the level of the individual.

There are inter-individual differences in susceptibility to the influence of early life experiences for which the underlying neurobiological mechanisms are poorly understood. Microglia play a role in environmental surveillance and may influence individual susceptibility to environmental factors. As an index of neurodevelopment, we estimated individual slopes of mean white matter fractional anisotropy (WM-FA) across three time-points (age 4.5, 6.0, and 7.5 years) for 351 participants. Individual variation in microglia reactivity was derived from an expression-based polygenic score(ePGS) comprised of Single Nucleotide Polymorphisms (SNPs) functionally related to the expression of microglia-enriched genes.A higher ePGS denotes an increased genetic capacity for the expression of microglia-related genes, and thus may confer a greater capacity to respond to the early environment and to influence brain development. We hypothesized that this ePGS would associate with the WM-FA index of neurodevelopment and moderate the influence of early environmental factors.Our findings show sex dependency, where a significant association between WM-FA and microglia ePGS was only obtained for females.We then examined associations with perinatal factors known to decrease (optimal birth outcomes and familial conditions) or increase (systemic inflammation) the risk for later mental health problems.In females, individuals with high microglia ePGS showed a negative association between systemic inflammation and WM-FA and a positive association between more advantageous environmental conditions and WM-FA. The microglia ePGS in females thus accounted for variations in the influence of the quality of the early environment on WM-FA.Finally, WM-FA slopes mediated the association of microglia ePGS with interpersonal problems and social hostility in females. Our findings suggest the genetic capacity for microglia function as a potential factor underlying differential susceptibility to early life exposuresthrough influences on neurodevelopment.

Accumbal µ-opioid receptors and salt taste-elicited hedonic responses in a rodent model of prenatal adversity, and their correlates using human functional genomics.

Prenatal adversity is associated with behavioral obesogenic features such as preference for palatable foods. Salt appetite may play a role in the development of adiposity and its consequences in individuals exposed to prenatal adversity, and sodium consumption involves individual differences in accumbal µ-opioid receptors function. We investigated the hedonic responses to salt and the levels of µ-opioid receptors and tyrosine hydroxylase in the nucleus accumbens (Nacc) of pups from an animal model of prenatal dietary restriction. In children, we evaluated the interaction between fetal growth and the genetic background associated with the accumbal µ-opioid receptor gene (OPRM1) expression on sodium consumption during a snack test. Sprague-Dawley dams were randomly allocated from pregnancy day 10 to receive an ad libitum (Adlib) or a 50% restricted (FR) diet. The pups' hedonic responses to a salt solution (NaCl 2%) or water were evaluated on the first day of life. FR and Adlib pups differ in their hedonic responses to salt, and there were decreased levels of accumbal µ-opioid and p-µ-opioid receptors in FR pups. In humans, a test meal and genotyping from buccal epithelial cells were performed in 270 children (38 intrauterine growth restricted-IUGR) at 4 years old from a Canadian prospective cohort (MAVAN). The OPRM1 genetic score predicted the sodium intake in IUGR children, but not in controls. The identification of mechanisms involved in the brain response to prenatal adversity and its consequences in behavioral phenotypes and risk for chronic diseases later in life is important for preventive and therapeutic purposes.

Associations between Social Adversity and Biomarkers of Inflammation, Stress, and Aging in Children.

BACKGROUND: Prior work has found relationships between childhood social adversity and biomarkers of stress, but knowledge gaps remain. To help address these gaps, we explored associations between social adversity and biomarkers of inflammation (interleukin-1ß [IL-1ß], IL-6, IL-8, tumor necrosis factor-alpha [TNF-α], and salivary cytokine hierarchical "clusters" based on the three interleukins), neuroendocrine function (cortisol, cortisone, dehydroepiandrosterone, testosterone, and progesterone), neuromodulation (N-arachidonoylethanolamine, stearoylethanolamine, oleoylethanolamide, and palmitoylethanolamide), and epigenetic aging (Pediatric-Buccal-Epigenetic clock). METHODS: We collected biomarker samples of children ages 0-17 recruited from an acute care pediatrics clinic and examined their associations with caregiver-endorsed education, income, social risk factors, and cumulative adversity. We calculated regression-adjusted means for each biomarker and compared associations with social factors using Wald tests. We used logistic regression to predict being in the highest cytokine cluster based on social predictors. RESULTS: Our final sample included 537 children but varied based on each biomarker. Cumulative social adversity was significantly associated with having higher levels of all inflammatory markers and with cortisol, displaying a U-shaped distribution. There were no significant relationships between cumulative social adversity and cortisone, neuromodulation biomarkers or epigenetic aging. CONCLUSION: Our findings support prior work suggesting that social stress exposures contribute to increased inflammation in children. IMPACT: Our study is one of the largest studies examining associations between childhood social adversity and biomarkers of inflammation, neuroendocrine function, neuromodulation, and epigenetic aging. It is one of the largest studies to link childhood social adversity to biomarkers of inflammation, and the first of which we are aware to link cumulative social adversity to cytokine clusters. It is also one of the largest studies to examine associations between steroids and epigenetic aging among children, and one of the only studies of which we are aware to examine associations between social adversity and endocannabinoids among children. CLINICAL TRIAL REGISTRATION: NCT02746393.

The brain insulin receptor gene network and associations with frailty index.

OBJECTIVE: To investigate longitudinal associations between variations in the co-expression-based brain insulin receptor polygenic risk score and frailty, as well as change in frailty across follow-up. METHODS: This longitudinal study included 1605 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network, which measure genetic variation in the function of the insulin receptor, were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Frailty was assessed in at baseline in 2001-2004, 2011-2013 and 2017-2018 by applying a deficit accumulation-based frailty index. Analyses were carried out by applying linear mixed models and logistical regression models adjusted for adult socioeconomic status, birthweight, smoking and their interactions with age. RESULTS: The FI levels of women were 1.19%-points (95% CI 0.12-2.26, P = 0.029) higher than in men. Both categorical and continuous hePRS-IR in women were associated with higher FI levels than in men at baseline (P < 0.05). In women with high hePRS-IR, the rate of change was steeper with increasing age compared to those with low or moderate hePRS-IR (P < 0.05). No associations were detected between mePRS-IR and frailty at baseline, nor between mePRS-IR and the increase in mean FI levels per year in either sex (P > 0.43). CONCLUSIONS: Higher variation in the function of the insulin receptor gene network in the hippocampus is associated with increasing frailty in women. This could potentially offer novel targets for future drug development aimed at frailty and ageing.

Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children.

Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the brain are fundamental for eliciting inhibitory control behaviors, but early markers of vulnerability to this behavioral trait are yet to be discovered. The gradual maturation of the prefrontal cortex (PFC), in particular of the mesocortical dopamine innervation, mirrors the protracted development of inhibitory control; both are present early in life, but reach full maturation by early adulthood. Evidence suggests the involvement of the Netrin-1/DCC signaling pathway and its associated gene networks in corticolimbic development. Here we investigated whether an expression-based polygenic score (ePRS) based on corticolimbic-specific DCC gene co-expression networks associates with impulsivity-related phenotypes in community samples of children. We found that lower ePRS scores associate with higher measurements of impulsive choice in 6-year-old children tested in the Information Sampling Task and with impulsive action in 6- and 10-year-old children tested in the Stop Signal Task. We also found the ePRS to be a better overall predictor of impulsivity when compared to a conventional PRS score comparable in size to the ePRS (4515 SNPs in our discovery cohort) and derived from the latest GWAS for ADHD. We propose that the corticolimbic DCC-ePRS can serve as a novel type of marker for impulsivity-related phenotypes in children. By adopting a systems biology approach based on gene co-expression networks and genotype-gene expression (rather than genotype-disease) associations, these results further validate our methodology to construct polygenic scores linked to the overall biological function of tissue-specific gene networks.

Omega-3 polygenic score protects against altered eating behavior in intrauterine growth-restricted children.

BACKGROUND: Alterations in eating behavior are common in infants with intrauterine growth restriction (IUGR); omega-3 polyunsaturated fatty acids (PUFA) could provide protection. We hypothesized that those born IUGR with a genetic background associated with increased production of omega-3-PUFA will have more adaptive eating behaviors during childhood. METHODS: IUGR/non-IUGR classified infants from MAVAN and GUSTO cohorts were included at the age of 4 and 5 years, respectively. Their parents reported child's eating behaviors using the child eating behavior questionnaire-CEBQ. Based on the GWAS on serum PUFA (Coltell 2020), three polygenic scores were calculated. RESULTS: Significant interactions between IUGR and polygenic score for omega-3-PUFA on emotional overeating (ß = -0.15, P = 0.049 GUSTO) and between IUGR and polygenic score for omega-6/omega-3-PUFA on desire to drink (ß = 0.35, P = 0.044 MAVAN), pro-intake/anti-intake ratio (ß = 0.10, P = 0.042 MAVAN), and emotional overeating (ß = 0.16, P = 0.043 GUSTO) were found. Only in IUGR, a higher polygenic score for omega-3-PUFA associated with lower emotional overeating, while a higher polygenic score for omega-6/omega-3-PUFA ratio was associated with a higher desire to drink, emotional overeating, and pro-intake/anti-intake. CONCLUSION: Only in IUGR, the genetic background for higher omega-3-PUFA is associated with protection against altered eating behavior, while the genetic score for a higher omega-6/omega-3-PUFA ratio is associated with altered eating behavior. IMPACT: A genetic background related to a higher polygenic score for omega-3 PUFA protected infants born IUGR against eating behavior alterations, while a higher polygenic score for omega-6/omega-3 PUFA ratio increased the risk of having eating behavior alterations only in infants born IUGR, irrespective of their adiposity in childhood. Genetic individual differences modify the effect of being born IUGR on eating outcomes, increasing the vulnerability/resilience to eating disorders in IUGR group and likely contributing to their risk for developing metabolic diseases later in life.

Diminished insulin sensitivity is associated with altered brain activation to food cues and with risk for obesity - Implications for individuals born small for gestational age.

While classically linked to memory, the hippocampus is also a feeding behavior modulator due to its multiple interconnected pathways with other brain regions and expression of receptors for metabolic hormones. Here we tested whether variations in insulin sensitivity would be correlated with differential brain activation following exposure to palatable food cues, as well as with variations in implicit food memory in a cohort of healthy adolescents, some of whom were born small for gestational age (SGA). Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was positively correlated with activation in the cuneus, and negatively correlated with activation in the middle frontal lobe, superior frontal gyrus and precuneus when presented with palatable food images versus non-food images in healthy adolescents. Additionally, HOMA-IR and insulinemia were higher in participants with impaired food memory. SGA individuals had higher snack caloric density and greater chance for impaired food memory. There was also an interaction between the HOMA-IR and birth weight ratio influencing external eating behavior. We suggest that diminished insulin sensitivity correlates with activation in visual attention areas and inactivation in inhibitory control areas in healthy adolescents. Insulin resistance also associated with less consistency in implicit memory for a consumed meal, which may suggest lower ability to establish a dietary pattern, and can contribute to obesity. Differences in feeding behavior in SGA individuals were associated with insulin sensitivity and hippocampal alterations, suggesting that cognition and hormonal regulation are important components involved in their food intake modifications throughout life.

Low socioeconomic status, parental stress, depression, and the buffering role of network social capital in mothers.

BACKGROUND: Pathways underlying the stress-depression relationship in mothers, and the factors that buffer this relationship are not well understood. AIMS: Drawing from the Stress Process model, this study examines (1) if parental stress mediates the association between socioeconomic characteristics and depressive symptoms, and (2) if social support and network capital moderate these pathways. METHOD: Data came from 101 mothers from Montreal. Generalized structural equation models were conducted, with depressive symptoms (CES-D scores) as the outcome, socioeconomic stressors as independent variables, parental stress as the mediator, and social support and network social capital as moderators. RESULTS: Parental stress partially mediated the association between household income and depressive symptoms (indirect effect: ß = -0.09, Bootstrap SE = 0.03, 95% CI = -0.15 to -0.03 p = 0.00). Network diversity moderated the relationship between parental stress and depressive symptoms (ß = -0.25, 95% CI = -0.42 to -0.09, p = 0.00); at high levels of stress, mothers with high compared to low network diversity reported fewer symptoms. CONCLUSION: Findings highlight the role that socioeconomic factors play in influencing women's risk of depression and shaping the benefits that ensue from social resources. Addressing these factors requires interventions that target the social determinants of depression.

Association of increased abdominal adiposity at birth with altered ventral caudate microstructure.

BACKGROUND: Neonatal adiposity is associated with a higher risk of obesity and cardiometabolic risk factors in later life. It is however unknown if central food intake regulating networks in the ventral striatum are altered with in-utero abdominal growth, indexed by neonatal adiposity in our current study. We aim to examine the relationship between striatal microstructure and abdominal adipose tissue compartments (AATCs) in Asian neonates from the Growing Up in Singapore Toward healthy Outcomes mother-offspring cohort. STUDY DESIGN: About 109 neonates were included in this study. Magnetic resonance imaging (MRI) was performed for the brain and abdominal regions between 5 to 17 days of life. Diffusion-weighted imaging of the brain was performed for the derivation of caudate and putamen fractional anisotropy (FA). Abdominal imaging was performed to quantify AATCs namely superficial subcutaneous adipose tissue (sSAT), deep subcutaneous adipose tissue (dSAT), and internal adipose tissue (IAT). Absolute and percentage adipose tissue of total abdominal volume (TAV) were calculated. RESULTS: We showed that AATCs at birth were significantly associated with increased FA in bilateral ventral caudate heads which are part of the ventral striatum (sSAT: ßleft = 0.56, p < 0.001; ßright = 0.65, p < 0.001, dSAT: ßleft = 0.43, p < 0.001; ßright = 0.52, p < 0.001, IAT: ßleft = 0.30, p = 0.005; ßright = 0.32, p = 0.002) in neonates with low birth weights adjusted for gestational age. CONCLUSIONS: Our study provides preliminary evidence of a potential relationship between neonatal adiposity and in-utero programming of the ventral striatum, a brain structure that governs feeding behavior.

Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children.

During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4 years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4 years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.

Salivary cytokine cluster moderates the association between caregivers perceived stress and emotional functioning in youth.

Some individuals exposed to early life stress show evidence of enhanced systemic inflammation and are at greater risk for psychopathology. In the current study, caregivers and their offspring (0-17 years) were recruited at a pediatric clinic visit at the University of California, San Francisco (UCSF). Mothers and seven-year-old children from the Growing Up inSingaporeTowards healthy Outcomes (GUSTO) prospective birth cohort were used as a replication cohort. Caregivers perceived stress was measured to determine potential intergenerational effects on the children's functioning and inflammation levels. Children's emotional functioning in the UCSF cohort was evaluated using the Pediatric Quality of Life (PedsQL) inventory. Child emotional and behavioral functioning was measured using the Child Behavior Checklist (CBCL) in GUSTO. Saliva was collected from the children and salivary levels of IL-6, IL-1ß, IL-8 and TNF-α were measured using an electrochemiluminescent cytokine multiplex panel. Child IL-6, IL-1ß, IL-8 cytokine levels were clustered into low, average, and high cytokine cluster groups using hierarchical cluster analysis. We did not find that salivary cytokine clusters were significantly associated with children's emotional or behavioral function. However, cytokine clusters did significantly moderate the association between increased caregiver perceived stress and reduced child emotional functioning (UCSF cohort) and increased Attention-Deficit-Hyperactivity (ADH) problems (GUSTO cohort, uncorrected Cohen's F2 = 0.02). Using a cytokine clustering technique may be useful in identifying those children exposed to increased caregiver perceived stress that are at risk of emotional and attention deficit hyperactivity problems.

Dopamine D4 receptor gene polymorphism (DRD4 VNTR) moderates real-world behavioural response to the food retail environment in children.

BACKGROUND: Evidence for the impact of the food retailing environment on food-related and obesity outcomes remains equivocal, but only a few studies have attempted to identify sub-populations for whom this relationship might be stronger than others. Genetic polymorphisms related to dopamine signalling have been associated with differences in responses to rewards such as food and may be candidate markers to identify such sub-populations. This study sought to investigate whether genetic variation of the dopamine D4 receptor gene (DRD4 exon III 48 bp VNTR polymorphism) moderated the association between local exposure to food retailers on BMI and diet in a sample of 4 to12-year-old children. METHODS: Data collected from a birth cohort and a community cross-sectional study conducted in Montreal, Canada, were combined to provide DRD4 VNTR polymorphism data in terms of presence of the 7-repeat allele (DRD4-7R) for 322 children aged between 4 and 12 (M (SD): 6.8(2.8) y). Outcomes were Body Mass Index (BMI) for age and energy density derived from a Food Frequency Questionnaire. Food environment was expressed as the proportion of local food retailers classified as healthful within 3 km of participants' residence. Linear regression models adjusted for age, sex, income, cohort, and geographic clustering were used to test gene*environment interactions. RESULTS: A significant gene*food environment interaction was found for energy density with results indicating that DRD4-7R carriers had more energy dense diets than non-carriers, with this effect being more pronounced in children living in areas with proportionally more unhealthy food retailers. No evidence of main or interactive effects of DRD4 VNTR and food environment was found for BMI. CONCLUSIONS: Results of the present study suggest that a genetic marker related to dopamine pathways can identify children with potentially greater responsiveness to unhealthy local food environment. Future studies should investigate additional elements of the food environment and test whether results hold across different populations.

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood.

BACKGROUND: Genetic variation in the guidance cue DCC gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the DCC coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume. METHODS: We filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with DCC in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual's genotype data, and then summarized into an ePRS. We evaluated associations between the DCC ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume. RESULTS: Higher ePRS was associated with higher total brain volume in children 8 to 10 years old (ß = 0.212, p = 0.043; n = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (ß = 0.101, p = 0.048; n = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function. LIMITATIONS: The relatively small sample size and age differences between the main and replication cohorts were limitations. CONCLUSION: Our findings suggest that the DCC coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.

Maternal antenatal depression and child mental health: Moderation by genomic risk for attention-deficit/hyperactivity disorder.

Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 × 10-4, R2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 × 10-9, R2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health.

Early environmental influences on the development of children's brain structure and function.

The developing brain in utero and during the first years of life is highly vulnerable to environmental influences. Experiences occurring during this period permanently modify brain structure and function through epigenetic modifications (alterations of the DNA structure and chromatin function) and consequently affect the susceptibility to mental disorders. In this review, we describe evidence linking adverse environmental variation during early life (from the fetal period to childhood) and long-term changes in brain volume, microstructure, and connectivity, especially in amygdala and hippocampal regions. We also describe genetic variations that moderate the impact of adverse environmental conditions on child neurodevelopment, such as polymorphisms in brain-derived neurotrophic factor and catechol-O-methyltransferase genes, as well as genetic pathways related to glutamate and monoaminergic signaling. Lastly, we have depicted positive early life experiences that could benefit childhood neurodevelopment and reverse some detrimental effects of adversity in the offspring. WHAT THIS PAPER ADDS: Prenatal, peripartum, and postnatal adversities influence child behavior and neurodevelopment. Exposure to environmental enrichment and positive influences may revert these effects. Putative mechanisms involve alterations in neurotrophic factors and neurotransmitter systems. New tools/big data improved the understanding on how early adversity alters neurodevelopment. This permits better translation/application of the findings from animal models to humans.

INFLUENCIAS AMBIENTALES TEMPRANAS EN EL DESARROLLO DE LA ESTRUCTURA Y FUNCIÓN DEL CEREBRO DE LOS NIÑOS: El cerebro en desarrollo en el útero y durante los primeros años de vida es altamente vulnerable a las influencias ambientales. Las experiencias que se producen durante este período modifican permanentemente la estructura y función del cerebro a través de modificaciones epigenéticas (alteraciones de la estructura del ADN y la función de la cromatina) y, por consiguiente, afectan la susceptibilidad a los trastornos mentales. En esta revisión, describimos la evidencia que vincula la variación ambiental adversa durante la vida temprana (desde el período fetal hasta la infancia) y los cambios a largo plazo en el volumen cerebral, la microestructura y la conectividad, especialmente en las regiones de la amígdala y el hipocampo. También describimos variaciones genéticas que moderan el impacto de las condiciones ambientales adversas en el desarrollo neurológico infantil, como los polimorfismos en los genes del factor neurotrófico derivado del cerebro y de la catecol-O-metiltransferasa, así como las vías genéticas relacionadas con el glutamato y la señalización monoaminérgica. Por último, hemos descrito experiencias positivas de la vida temprana que podrían beneficiar el desarrollo neurológico infantil y revertir algunos efectos perjudiciales de la adversidad en la descendencia.

INFLUÊNCIAS AMBIENTAIS PRECOCES NO DESENVOLVIMENTO DA ESTRUTURA E FUNÇÃO CEREBRAL EM CRIANÇAS: O cérebro em desenvolvimento no útero e durante os primeiros anos devida é altamente vulnerável a influências ambientais. Experiências que ocorrem durante este período modificam permanentemente a estrutura e função cerebrais por meio de modificações epigenéticas (alterações da estrutura do DNA e função da cromatina). Consequentemente, afetam a suscetibilidade a desordens mentais. Nesta revisão, nós descrevemos a evidência relacionando variação ambiental adversa durante o início da vida (do período fetal à infância) e mudanças de longo prazo no volume, microestrutura e conectividade cerebral, especialmente nas regiões da amídala e hipocampo. Também descrevemos variações genéticas que moderam o impacto de condições ambientais adversas no neurodesenvolvimento infantil, tais como polimorfismos em fatores neurotróficos derivados do cérebro, e genes catechol-O-metiltransferases, assim como vias genéticas ligadas à sinalização por glutamato e momonoaminérgica. Por fim, descrevemos experiências precoces positivas que podem beneficiar o neurodesenvolvimento infantil e reverter alguns efeitos detrimentais da adversidade na prole.

Polygenic differential susceptibility to prenatal adversity.

A recent article in this journal reported a number of gene × environment interactions involving a serotonin transporter-gene network polygenic score and a composite index of prenatal adversity predicting several problem behavior outcomes at 48 months (e.g., anxious/depressed, pervasive developmental problems) and at 60 months (e.g., withdrawal, internalizing problems), yet did not illuminate the nature or form these genetic × environment interactions took. Here we report results of six additional analyses to evaluate whether these interactions reflected diathesis-stress or differential-susceptibility related processes. Analyses of the regions of significance and proportion of interaction index are consistent with the diathesis-stress model, seemingly because of the truncated nature of the adversity score (which did not extend to supportive/positive prenatal experiences/exposures); in contrast, the proportion (of cases) affected index favors the differential-susceptibility model. These results suggest the need for future studies to extend measurement of the prenatal environment to highly supportive experiences and exposures.

PRS-on-Spark (PRSoS): a novel, efficient and flexible approach for generating polygenic risk scores.

BACKGROUND: Polygenic risk scores (PRS) describe the genomic contribution to complex phenotypes and consistently account for a larger proportion of variance in outcome than single nucleotide polymorphisms (SNPs) alone. However, there is little consensus on the optimal data input for generating PRS, and existing approaches largely preclude the use of imputed posterior probabilities and strand-ambiguous SNPs i.e., A/T or C/G polymorphisms. Our ability to predict complex traits that arise from the additive effects of a large number of SNPs would likely benefit from a more inclusive approach. RESULTS: We developed PRS-on-Spark (PRSoS), a software implemented in Apache Spark and Python that accommodates different data inputs and strand-ambiguous SNPs to calculate PRS. We compared performance between PRSoS and an existing software (PRSice v1.25) for generating PRS for major depressive disorder using a community cohort (N = 264). We found PRSoS to perform faster than PRSice v1.25 when PRS were generated for a large number of SNPs (~ 17 million SNPs; t = 42.865, p = 5.43E-04). We also show that the use of imputed posterior probabilities and the inclusion of strand-ambiguous SNPs increase the proportion of variance explained by a PRS for major depressive disorder (from 4.3% to 4.8%). CONCLUSIONS: PRSoS provides the user with the ability to generate PRS using an inclusive and efficient approach that considers a larger number of SNPs than conventional approaches. We show that a PRS for major depressive disorder that includes strand-ambiguous SNPs, calculated using PRSoS, accounts for the largest proportion of variance in symptoms of depression in a community cohort, demonstrating the utility of this approach. The availability of this software will help users develop more informative PRS for a variety of complex phenotypes.

Low birth weight is associated with increased fat intake in school-aged boys.

Evidence suggests that both high and low birth weight children have increased the risk for obesity and the metabolic syndrome in adulthood. Previously we have found altered feeding behaviour and food preferences in pre-school children and adults born with low birth weight. In this study, we investigated if birth weight was associated with different intake of fat, carbohydrate and/or protein at 6-12 years of age. This is a cross-sectional study where 255 guardians answered online and telephone questions including anthropometrics and demographic data, parental family food rules (food control, encouragement and restriction) and a complete web-based FFQ for their children (130 boys and 125 girls). Baseline demographic and parental food rules characteristics did not differ accordingly to sex. Linear regression models were conducted separately for each sex, adjusted for income, age and maternal age. There were no differences in total energy intake, but energy density (ED, energy content/g) was negatively associated with birth weight in boys. Macronutrient analysis showed that ED intake was from a greater intake of fat. Birth weight was not a significant predictor of protein and carbohydrate intake in boys. In girls, we saw a positive correlation between fat intake and cholesterol intake v. birth weight, but no association with ED intake (results did not remain after adjustment). The study shows that low birth weight is associated with altered fat intake in childhood in a sex-specific manner. It is likely that biological factors such as fetal programming of homoeostatic and/or hedonic pathways influencing food preferences are involved in this process.

The early care environment and DNA methylome variation in childhood.

Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.

Fetal growth interacts with multilocus genetic score reflecting dopamine signaling capacity to predict spontaneous sugar intake in children.

BACKGROUND: We have shown that intrauterine growth restriction (IUGR) leads to increased preference for palatable foods at different ages in both humans and rodents. In IUGR rodents, altered striatal dopamine signaling associates with a preference for palatable foods. OBJECTIVES: Our aim was to investigate if a multilocus genetic score reflecting dopamine-signaling capacity is differently associated with spontaneous palatable food intake in children according to the fetal growth status. METHODS: 192 four-year old children from a community sample from Montreal and Hamilton, Canada, were classified according to birth weight and administered a snack test meal containing regular as well as palatable foods. Intrauterine growth restriction was based on the birth weight ratio below 0.85; children were genotyped for polymorphisms associated with dopamine (DA) signaling, with the hypofunctional variants (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10-repeat, Met/Met-COMT) receiving the lowest scores, and a composite score was calculated reflecting the total number of the five genotypes. Macronutrient intake during the Snack Test was the outcome. RESULTS: Adjusting for z-score BMI at 48 months and sex, there was a significant interaction of the genetic profile and fetal growth on sugar intake [߈ = -4.56, p = 0.04], showing a positive association between the genetic score and sugar intake in IUGR children, and no association in non-IUGR children. No significant interactions were seen in other macronutrients. CONCLUSIONS: Variations in a genetic score reflecting DA signaling are associated with differences in sugar intake only in IUGR children, suggesting that DA function is involved in this behavioral feature in these children. This may have important implications for obesity prevention in this population.