Association of Childhood Chronic Physical Aggression with a DNA Methylation Signature in Adult Human T Cells

Background

Chronic physical aggression (CPA) is characterized by frequent use of physical aggression from early childhood to adolescence. Observed in approximately 5% of males, CPA is associated with early childhood adverse environments and long-term negative consequences. Alterations in DNA methylation, a covalent modification of DNA that regulates genome function, have been associated with early childhood adversity.

Aims

To test the hypothesis that a trajectory of chronic physical aggression during childhood is associated with a distinct DNA methylation profile during adulthood.

Methods

We analyzed genome-wide promoter DNA methylation profiles of T cells from two groups of adult males assessed annually for frequency of physical aggression between 6 and 15 years of age: a group with CPA and a control group. Methylation profiles covering the promoter regions of 20 000 genes and 400 microRNAs were generated using MeDIP followed by hybridization to microarrays.

Results

In total, 448 distinct gene promoters were differentially methylated in CPA. Functionally, many of these genes have previously been shown to play a role in aggression and were enriched in biological pathways affected by behavior. Their locations in the genome tended to form clusters spanning millions of bases in the genome.

Conclusions

This study provides evidence of clustered and genome-wide variation in promoter DNA methylation in young adults that associates with a history of chronic physical aggression from 6 to 15 years of age. However, longitudinal studies of methylation during early childhood will be necessary to determine if and how this methylation variation in T cells DNA plays a role in early development of chronic physical aggression.     

DNA Methylation Signature of Childhood Chronic Physical Aggression in T Cells of Both Men and Women

Background

High frequency of physical aggression is the central feature of severe conduct disorder and is associated with a wide range of social, mental and physical health problems. We have previously tested the hypothesis that differential DNA methylation signatures in peripheral T cells are associated with a chronic aggression trajectory in males. Despite the fact that sex differences appear to play a pivotal role in determining the development, magnitude and frequency of aggression, most of previous studies focused on males, so little is known about female chronic physical aggression. We therefore tested here whether or not there is a signature of physical aggression in female DNA methylation and, if there is, how it relates to the signature observed in males.

Methodology/Principal Findings

Methylation profiles were created using the method of methylated DNA immunoprecipitation (MeDIP) followed by microarray hybridization and statistical and bioinformatic analyses on T cell DNA obtained from adult women who were found to be on a chronic physical aggression trajectory (CPA) between 6 and 12 years of age compared to women who followed a normal physical aggression trajectory. We confirmed the existence of a well-defined, genome-wide signature of DNA methylation associated with chronic physical aggression in the peripheral T cells of adult females that includes many of the genes similarly associated with physical aggression in the same cell types of adult males.

Conclusions

This study in a small number of women presents preliminary evidence for a genome-wide variation in promoter DNA methylation that associates with CPA in women that warrant larger studies for further verification. A significant proportion of these associations were previously observed in men with CPA supporting the hypothesis that the epigenetic signature of early life aggression in females is composed of a component specific to females and another common to both males and females.     

A turning point for Alzheimer's disease?

Despite an archive of over 73,000 research papers published in the last two decades on the subject of Alzheimer's disease (AD), little clinical progress has been made relative to how people get sporadic AD and what can be done to help them avoid it. This review spotlights strategic steps that could be a turning point in the dramatic lowering of Alzheimer prevalence. The main strategy includes application of four pillars of prevention: 1) early identification of AD vascular risk factors; 2) early detection of AD vascular risk factors; 3) early intervention of AD vascular risk factors based on evidence-based medical decisions; 4) patient follow-up to assess and modify interventions as needed. Tandem to these four pillars of prevention, a proactive lifestyle consisting of a healthy diet coupled to physical and mental activity should be applied as part of any therapeutic intervention. We are persuaded by mounting and compelling evidence that AD is a multifactorial disorder kindled by vascular risk factors that generate chronic brain hypoperfusion (CBH) during advanced aging. A pathobiological cascade of biochemical events in the presence of CBH that leads to oxidative stress and neurodegeneration appears to involve multiple biofactors including micronutrients, trace metals, lipids, and pro-oxidants, as reviewed in this special issue of BioFactors. Modulation of these biofactors may help prevent or control incipient AD. ? 2012 International Union of Biochemistry and Molecular Biology, Inc.     

Wisconsin Twin Panel.

The Wisconsin Twin Panel was initiated in 1994 to serve a study of the development of childhood mood and behavioral disorders. Families who give birth to twins within the state of Wisconsin are recruited within 6 months of the birth. The panel currently supports three ongoing, longitudinal research projects. Research foci include studying epigenetic contributions to emotional, physical, cognitive, and motoric development of infant and toddler twins; physiological concomitants of childhood temperament; and early risk and resiliency factors related to child psychopathology. All three studies include videotaped observational assessments and biological measures.     

Investing in early human development: Timing and economic efficiency

Policy discussions to ameliorate socioeconomic (SES) inequalities are increasingly focused on investments in early childhood. Yet such interventions are costly to implement, and clear evidence on the optimal time to intervene to yield a high economic and social return in the future is meagre. The majority of successful early childhood interventions start in the preschool years. However socioeconomic gradients in cognitive skills, socio-emotional functioning and health can be observed by age three, suggesting that preventative programmes starting earlier in childhood may be even more effective. We discuss the optimal timing of early childhood intervention with reference to recent research in developmental neuroscience. We motivate the need for early intervention by providing an overview of the impact of adverse risk factors during the antenatal and early childhood periods on outcomes later in life. We provide a brief review of the economic rationale for investing early in life and propose the “antenatal investment hypothesis”. We conclude by discussing a suite of new European interventions that will inform this optimal timing debate.     

Focus: Allergic Diseases and Type II Immunity: Allergy Prevention: An Overview of Current Evidence

Background: There has been a rapid rise in allergic disorders across the globe. This has increased research into the determinants of allergy development, to identify factors that may be manipulated to mitigate risk. An opportune window in immunological development appears to exist in early life whereby certain exposures may promote or prevent the development of an allergic disposition. Furthermore, factors that affect the composition and diversity of the microbiome in early life have been explored. In this review, we discuss current literature and recommendations relating to exposures that may prevent allergy development or promote tolerance. Risk factors and recommendations: Delivery by caesarean section, omission of breastfeeding, vitamin D insufficiency, and environmental exposures, such as cigarette smoke exposure, all increase the risk of an allergic predisposition. Dietary diversity during pregnancy, lactation, and in infancy is protective. Breastfeeding for at least 4 months reduces the risk of eczema. Recommendations for food-allergen exposure has shifted from delayed introduction to early introduction as a tolerance-inducing strategy. Supplements such as probiotics and vitamins during pregnancy and infancy have yet to produce conclusive results for allergy prevention. Emollient use in infancy has not been shown to be protective against eczema or food allergy.     

Aggression in young children with concurrent callous–unemotional traits: can the neurosciences inform progress and innovation in treatment approaches?

Parenting is the 'clean water' of healthy psychological development and parenting interventions remain the number one treatment at the individual and community levels for early-onset aggression and antisocial behaviour in children. However, recent progress in child psychopathology research is specifying a number of biological mechanisms that interact with environmental risk to influence pathways into aggression and antisocial behaviour. After a brief review of the parent training literature, we focus on child factors, especially callous-unemotional traits, that parse 'aggressive' children into more homogeneous groupings, and then review selected ideas about the origins of aggression coming from the neurosciences (such as neurobehavioural responsivity to emotional stimuli; hypothalamic-pituitary axis abnormalities influencing low cortisol and low serotonin production). We review human and, where relevant, animal models of neurobiological system changes with particular attention to developmental timing and interactions with environmental factors, especially parenting. Based on this innovative research, we then discuss a number of ideas that hold potential for interventions. We conclude that the future will see the development of interventions that aim for synergy between specific biological processes and psychological experiences as they unfold developmentally. The use of D-cycloserine in fear extinction and oxytocin in affiliative bonds is used as an example of these futuristic approaches.     

Do early life factors affect the development of knee osteoarthritis in later life: a narrative review

Osteoarthritis (OA) mainly affects older populations; however, it is possible that early life factors contribute to the development of OA in later life. The aim of this review is to describe the association between childhood or early adulthood risk factors and knee pain, structural imaging markers and development of knee OA in later life. A narrative overview of the literature synthesising the findings of literature retrieved from searches of computerised databases and manual searches was conducted. We found that only a few studies have explored the long-term effect of childhood or early adulthood risk factors on the markers of joint health that predispose people to OA or joint symptoms. High body mass index (BMI) and/or overweight status from childhood to adulthood were independently related to knee pain and OA in later life. The findings regarding the association between strenuous physical activity and knee structures in young adults are still conflicting. However, a favourable effect of moderate physical activity and fitness on knee structures is reported. Childhood physical activity and performance measures had independent beneficial effects on knee structures including knee cartilage in children and young adults. Anterior knee pain syndrome in adolescence could lead to the development of patellofemoral knee OA in the late 40s. Furthermore, weak evidence suggests that childhood malalignment, socioeconomic status and physical abuse are associated with OA in later life. The available evidence suggests that early life intervention may prevent OA in later life.     

Epigenetic Modifications Linked to T2D,the Heritability Gap,and Potential Therapeutic Targets

With the pandemic of type 2 diabetes (T2D), there is an ever-increasing need to fully understand the underlying mechanisms of the disease. Type 2 diabetes shows a high heritability risk (25–80%); however, genes account only for 10% of this risk. From all the risk factors for diabetes, epigenetic mechanisms have the highest statistical scoring in explaining the disease. A multitude of organ-specific epigenomic changes have been linked to type 2 diabetes. Nutritional influences, mainly in the early life, physical activity level, environmental toxins act as epigenetic factors and the recognized epigenetic changes can represent a therapeutical target, new drugs being currently in development for this application. Our current review focuses on the most common epigenetic modifications linked to type 2 diabetes or insulin resistance, the potentially emerging epigenetic-related interventions and pharmacoepigenetic knowledge.     

Vitamin D deficiency in children with cerebral palsy: A narrative review of epidemiology,contributing factors,clinical consequences and interventions

Sufficient vitamin D levels are necessary, not only for mineralization, normal growth and development of bones, but also for the prevention of fatal chronic diseases like diabetes mellitus, metabolic syndrome and cancer. This is of particular importance in children with neuro- and musculoskeletal disorders, especially cerebral palsy (CP). CP is a heterogeneous group of childhood developmental disability disorders described by uncharacteristic posture, balance, and movement. Patients with CP are at an increased risk of vitamin D deficiency and as a result reduced bone mineral density, bone fragility, osteopenia, and rickets. The present review aims to combine and summarize available evidence, regarding the epidemiology, underlying contributing factors, clinical consequences, and treatment interventions of vitamin D deficiency in children with CP.     

Reprogramming DNA methylation in the preimplantation stage: peeping with Dolly's eyes

Oocyte cytoplasmic factors can reprogramme the sperm genome during fertilisation or the somatic cell genome during cloning. Diverse reprogramming machinery acts sequentially and interdependently on the imported genome to drive it to totipotency, but their three-dimensional interactions in the cytoplasm remain unknown. Aberrant epigenetic phenomena in early cloned embryos indicate that parts of the somatic cell genome are unyielding to reprogramming forces, owing to their 'knotty' epigenetic features. This fastidious nature of the donor genome might prevent completion of epigenetic reprogramming. It might also help to explain the chronic developmental defects seen in many cloned embryos.     

Explanatory Models of Female Pubertal Timing: Discordances Between Cultural Models of Maturation and the Recollection and Interpretation of Personal Developmental Experiences

Given the ambiguity surrounding the source of the continuing trend toward earlier menarche observed in Westernized nations, several competing explanatory models have emerged regarding variation in pubertal timing. While a biomedical model proposes that predominantly constitutional characteristics shape the maturation timetable, an alternative framework derived from Life History Theory (LHT) evolutionary principles emphasizes the influence of psychosocial factors on development. Working with a sample of women 19?C25?years of age (N?=?103) drawn from two Southeastern U.S. colleges, we combined cultural consensus analysis with retrospective self-report regarding childhood stress and menarcheal timing to investigate whether reported developmental experiences align with cultural models regarding factors that should drive pubertal timing. Results suggest a robust cultural model consistent with a biomedical framework concentrating principally on constitutional characteristics. However, participants?? personal developmental recollections support an association between higher childhood stress and earlier menarche. These findings support LHT predictions that early reproductive maturation is an evolutionary adaptive response to chronic childhood stress as well as clarify the extent to which cultural models of factors contributing to puberty concord with developmental experiences.     

Early Risk Factors of Overweight Developmental Trajectories during Middle Childhood

Background

Research is needed to identify early life risk factors associated with different developmental paths leading to overweight by adolescence.

Objectives

To model heterogeneity in overweight development during middle childhood and identify factors associated with differing overweight trajectories.

Methods

Data was drawn from the Quebec Longitudinal Study of Child Development (QLSCD; 1998-2010). Trained research assistants measured height and weight according to a standardized protocol and conducted yearly home interviews with the child’s caregiver (mother in 98% of cases). Information on several putative early life risk factors for the development of overweight were obtained, including factors related to the child’s perinatal, early behavioral family and social environment. Group-based trajectories of the probability of overweight (6-12 years) were identified with a semiparametric method (n=1678). Logistic regression analyses were used to identify early risk factors (5 months- 5 years) associated with each trajectory.

Results

Three trajectories of overweight were identified: “early-onset overweight” (11.0 %), “late-onset overweight” (16.6%) and “never overweight” (72.5%). Multinomial analyses indicated that children in the early and late-onset group, compared to the never overweight group, had 3 common types of risk factors: parental overweight, preschool overweight history, and large size for gestational age. Maternal overprotection (OR= 1.12, CI: 1.01-1.25), short nighttime sleep duration (OR=1.66, CI: 1.07-2.57), and immigrant status (OR=2.01, CI: 1.05-3.84) were factors specific to the early-onset group. Finally, family food insufficiency (OR=1.81, CI: 1.00-3.28) was weakly associated with membership in the late-onset trajectory group.

Conclusions

The development of overweight in childhood follows two different trajectories, which have common and distinct risk factors that could be the target of early preventive interventions.     

Developmental plasticity and developmental origins of non-communicable disease: theoretical considerations and epigenetic mechanisms

There is now evidence that developmental influences have lifelong effects on cardiovascular and metabolic function and that elements of the heritable or familial component of susceptibility to cardiovascular disease, obesity and other non-communicable diseases (NCD) can be transmitted across generations by non-genomic means. In animals the developmental environment induces altered phenotypes through genetic, physiological (especially endocrine) and epigenetic mechanisms. The latter include DNA methylation, covalent modifications of histones and non-coding RNAs. Such ‘tuning’ of phenotype has potential adaptive value and may confer Darwinian fitness advantage because it either adjusts the phenotype to current circumstances and/or attempts to match an individual’s responses to the environment predicted to be experienced later. When the phenotype is mismatched to the later environment, e.g. from inaccurate nutritional cues from the mother or placenta before birth, or from rapid environmental change through improved socio-economic conditions, risk of NCD increases. Such mechanisms are also thought to play roles in ageing and early onset of puberty, reinforcing a life-course perspective on such adaptive responses, especially the detrimental later effects of trade-offs. Epigenetic changes induced during development are highly gene-specific and function at the level of individual CpG dinucleotides in both gene promoter and intergenic regions. Evidence is accruing that endocrine or nutritional interventions during early postnatal life can reverse epigenetic and phenotypic changes induced, for example, by unbalanced maternal diet during pregnancy. Elucidation of epigenetic processes may permit perinatal identification of individuals most at risk of later NCD and enable early intervention strategies to reduce such risk.     

Biomarkers and clinical staging in psychiatry

Personalized medicine is rapidly becoming a reality in today's physical medicine. However, as yet this is largely an aspirational goal in psychiatry, despite significant advances in our understanding of the biochemical, genetic and neurobiological processes underlying major mental disorders. Preventive medicine relies on the availability of predictive tools; in psychiatry we still largely lack these. Furthermore, our current diagnostic systems, with their focus on well‐established, largely chronic illness, do not support a pre‐emptive, let alone a preventive, approach, since it is during the early stages of a disorder that interventions have the potential to offer the greatest benefit. Here, we present a clinical staging model for severe mental disorders and discuss examples of biological markers that have already undergone some systematic evaluation and that could be integrated into such a framework. The advantage of this model is that it explicitly considers the evolution of psychopathology during the development of a mental illness and emphasizes that progression of illness is by no means inevitable, but can be altered by providing appropriate interventions that target individual modifiable risk and protective factors. The specific goals of therapeutic intervention are therefore broadened to include the prevention of illness onset or progression, and to minimize the risk of harm associated with more complex treatment regimens. The staging model also facilitates the integration of new data on the biological, social and environmental factors that influence mental illness into our clinical and diagnostic infrastructure, which will provide a major step forward in the development of a truly pre‐emptive psychiatry.     

Postnatal Cranial Development in Papionin Primates: An Alternative Model for Hominin Evolutionary Development

The evolution of hominin growth and life history has long been a subject of intensive research, but it is only recently that paleoanthropologists have considered the ontogenetic basis of human morphological evolution. To date, most human EvoDevo studies have focused on developmental patterns in extant African apes and humans. However, the Old World monkey tribe Papionini, a diverse clade whose members resemble hominins in their ecology and population structure, has been proposed as an alternative model for human craniofacial evolution. This paper reviews prior studies of papionin development and socioecology and presents new analyses of juvenile shape variation and ontogeny to address fundamental questions concerning primate cranial development, including: (1) When are cranial shape differences between species established? (2) How do epigenetic influences modulate early-arising pattern differences? (3) How much do postnatal developmental trajectories vary? (4) What is the impact of developmental variation on adult cranial shape? and, (5) What role do environmental factors play in establishing adult cranial form? Results of this inquiry suggest that species differences in cranial morphology arise during prenatal or earliest postnatal development. This is true even for late-arising features that develop under the influence of epigenetic factors such as mechanical loading. Papionins largely retain a shared, ancestral pattern of ontogenetic shape change, but large size and sexual dimorphism are associated with divergent developmental trajectories, suggesting differences in cranial integration. Developmental simulation studies indicate that postnatal ontogenetic variation has a limited influence on adult cranial morphology, leaving early morphogenesis as the primary determinant of cranial shape. The ability of social factors to influence craniofacial development in Mandrillus suggests a possible role for phentotypic plasticity in the diversification of primate cranial form. The implications of these findings for taxonomic attribution of juvenile fossils, the developmental basis of early hominin characters, and hominin cranial diversity are discussed.     

Physical Aggression and Language Ability from 17 to 72 Months: Cross-Lagged Effects in a Population Sample

Background

Does poor language ability in early childhood increase the likelihood of physical aggression or is language ability delayed by frequent physical aggression? This study examined the longitudinal associations between physical aggression and language ability from toddlerhood to early childhood in a population sample while controlling for parenting behaviours, non-verbal intellectual functioning, and children’s sex.

Methods

Children enrolled in the Quebec Longitudinal Study of Child Development (QLSCD) (N = 2, 057) were assessed longitudinally from 17 to 72 months via parent reports and standardized assessments.

Results

The cross-lagged models revealed modest reciprocal associations between physical aggression and language performance from 17 to 41 months but not thereafter.

Conclusions

Significant associations between physical aggression and poor language ability are minimal and limited to the period when physical aggression and language performance are both substantially increasing. During that period parenting behaviours may play an important role in supporting language ability while reducing the frequency of physical aggression. Further studies are needed that utilize multiple assessments of physical aggression, assess multiple domains of language abilities, and that examine the potential mediating role of parenting behaviours between 12 and 48 months.     

Disordered eating attitudes and behaviors in overweight youth

Disordered eating attitudes and behaviors appear to be quite common in youth, and overweight youth have been identified as a subset of the population at particularly high risk for endorsing such symptoms. Overweight and eating disorder (ED) symptomatology independently confer significant threats to one's physical and psychosocial health, showing strong links with body weight gain and risk for ED development. When concurrent, the risk for negative health outcomes may be compounded. The purpose of this article is to review the current state of the literature as it concerns disordered eating and its correlates in overweight children and adolescents. Extant literature on the prevalence, distribution, correlates, and etiology of disordered eating attitudes and behaviors (i.e., negative attitudes toward shape and weight, unhealthy weight control behaviors, and binge eating) in overweight youth is reviewed and consolidated in order to make assessment and treatment recommendations for healthcare providers. The current literature suggests that early detection of disordered eating in overweight youth should be a priority to provide appropriate intervention, thereby helping to slow the trajectory of weight gain and prevent or reduce the long-term negative consequences associated with both conditions. Future research should focus on explicating developmental pathways, and on developing novel prevention and treatment interventions for overweight youth exhibiting disordered eating patterns.