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Objective: To study familial and nonfamilial environmental influences on attention problems and attention-deficit/hyperactivity disorder (ADHD) in monozygotic twins discordant and concordant-high and low for these traits. Method: Ninety-five twin pairs from The Netherlands Twin Register were selected. Longitudinal survey data were collected at 1, 2, 3, 5, 7, 10, and 12 years from parents, twins, and teachers. Mothers participated in a structured clinical interview when twins were between 10 and 17 years of age. Results: Affected twins from discordant pairs scored higher than unaffected cotwins on multiple measures of attention problems, ADHD, and other behavior problems according to mother, teacher, and self. Behavioral discordance was evident at age 2 and all subsequent measurements. Compared with unaffected cotwins, affected twins had lower birth weight and delayed physical growth and motor development. Differences between discordant and concordant groups were reported for maternal smoking, sleeping in different rooms, and living with only one parent. Conclusions: Significant markers of ADHD are found in infancy and include low birth weight and delayed motor development. As the knowledge of specific genetic and environmental influences on ADHD increases, future studies may focus on their complex interplay. (Contains 1 table and 4 figures.)

Objective: To estimate the genetic and environmental contributions to oppositional defiant behavior (ODB) from mother, father, and teacher report using the Conners Revised Short Forms in a large twin sample. Method: ODB data were collected from 1,595 mothers, 1,114 fathers, and 793 teachers of 7-year-old twin pairs from the Netherlands Twin Registry in the 1990-1992 cohort with an 80% response rate. Models were fit for each informant to determine the genetic, environmental, gender, and informant influences on ODB. Results: Genetic analyses of the ODB quantitative scale showed additive genetic (A) by mother (55%), by father (57%), and by teacher (21% girls, 38% boys) unique environmental (E) (mother, 22%; father, 29%; teacher, 48% girls, 39% boys) and shared environmental (C) (mother, 14%; father, 23%; teacher, 31% girls, 23% boys) influences. Conclusions: Additive genetic and unique environmental factors account for the majority of the influences on ODB for boys and girls by all informants.

A study of the adult outcomes of children who exhibited severe problems with self-regulation defined as being concurrently rated highly on the Child Behavior Checklist-Dysregulation Profile (CBCL-DP) is presented. The manifestation of CBCL-DP at wave 1 was linked to increased rates of adult anxiety disorders, disruptive behavior disorders, mood disorders, and drug abuse 14 years later.

The relationship between polymorphism in the catechol-O-methyltransferase gene and aggressive behavior and attention problems in youth are studied. Youth carrying a methionine allele are associated with higher average aggressive behavior scores.

Advances in the field of child psychiatric genetics since the drafting of the human genome are described. Research on the genetics of developmental psychopathology has grown exponentially during this period.

A sample of Dutch boys aged 7, 10 and 12 is examined to determine the differences and subtypes of attention problems in attention-deficit/hyperactivity disorder. Findings show mild, moderate and severe attention problem subtypes and their interpretations with regard to nervous behavior, hyperactivity/impulsivity, and inattentiveness/dreaminess.

The involvement of genetic and environmental factors to the development of obsessive compulsion symptoms during the adolescent period is examined. Study revealed that individual differences in OC symptoms are heritable during puberty and shared environmental influences played a role only in the beginning of adolescence but no sex differences in heritability estimations were found during this period.

The study applies latent profiles analysis to a group of children and adolescents to test temperament phenotypes in order to examine their association to wellness and psychopathology. One of the results concluded that lifetime disorder was lower in the steady class as compared to moderate class.

Ethnical violations involving conflict of interest having a significant negative in assessment and treatment of children with psychiatric disorder is discussed. Financial conflict of interest is the most worried but by no means the only one.

Psychiatrist Richard D. Todd spent almost 25 years studying the genetic and environmental factors that affect child psychiatric disorders. Todd died of leukemia on August 22, 2008 and is survived by his wife and his long-time collaborator Dr. Karen O'Malley.

Objective: The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis., Method: Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated., Results: SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96., Conclusion: The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants., Competing Interests: Dr. Hudziak has received grant or research support from the National Institutes of Health, the National Institute of Mental Health, the National Institute of Diabetes and Digestive and Kidney Disease, and the state of Vermont. His primary appointment is with the University of Vermont. He has additional appointments with Erasmus University in Rotterdam, Netherlands, Washington University School of Medicine in St. Louis, Missouri, and the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire. Drs. Middeldorp, Groen-Blokhuis, St Pourcain, Greven, Pappa, Tiesler, Nolte, Ebejer, Zhao, Davies, Ehli, Evans, Guxens, Hottenga, Jugessur, Kemp, Martin, Myhre, Ormel, Ring, Standl, Stergiakouli, Stoltenberg, Thiering, Timpson, Trzaskowski, van der Most, Nyholt, Medland, Neale, Jacobsson, Sunyer, Hartman, Whitehouse, Pennell, Heinrich, Plomin, Smith, Tiemeier, Posthuma, Boomsma, Ms. Hammerschlag, Mr. Ouwens, Mr. Ang, Ms. Vilor-Tejedor, Mr. Bacelis, Ms. Fedko, Ms. Krapohl, Mr. Murcia, and Ms. Wang report no biomedical financial interests or potential conflicts of interest., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: The consequences of bullying are well described, yet little is known about protective factors that may diminish the negative sequelae. One possible factor, physical activity (PA), improves mental health in general and clinical populations. The purpose of this study is to examine relationships among PA, sadness, and suicidality in bullied US adolescents. We hypothesized that physically active students would be less likely to feel sad or to report suicidal ideation or attempts, including bullied students., Method: Using the 2013 National Youth Risk Behavior Survey (N = 13,583), regression models adjusted for age, sex, and race estimated the odds ratios among PA, sadness, suicidal ideation, and suicide attempts, stratified by whether students were bullied., Results: Overall, 30.0% of students reported sadness for 2 or more weeks, 22.2% reported suicidal ideation, and 8.2% reported suicide attempt in the previous 12 months. Bullied students were twice as likely to report feeling sad and 3 times as likely to report suicidal ideation or attempt. Students who reported exercising 4 to 5 days a week had lower adjusted odds of sadness, suicidal ideation, or suicide attempts than students who exercised 0 to 1 day a week (p ≤ .0001). After stratifying by bullying, similar but attenuated associations were observed. Overall, exercise for 4 or more days per week was associated with an approximate 23% reduction in suicidal ideation and attempt in bullied students., Conclusion: PA is inversely related to sadness and suicidality in adolescents, highlighting the relationship between PA and mental health in children, and potentially implicating PA as a salient option in the response to bullying in schools., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: The Research Domain Criteria (RDoC) project was initiated to develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures. This article reviews the rationale behind the RDoC program, its goals, and central tenets; discusses application of an RDoC framework to research with maltreated children; and highlights some clinical implications of this work., Method: Published RDoC papers were reviewed, together with relevant preclinical and clinical studies that guide our work on risk and resilience in maltreated children., Results: The ultimate long-term goal of the RDoC initiative is precision medicine in psychiatry. In the interim, the RDoC initiative provides a framework to organize research to help develop the database required to derive a new psychiatric nomenclature that can appropriately match treatments to patients. The primary focus of RDoC is on neural circuitry, with levels of analyses that span from molecules to behavior. There has been some concern that the RDoC framework is reductionist, with an overemphasis on neural circuits and genetics; however, the briefly reviewed, burgeoning literature on neuroplasticity and epigenetics highlights that this concern is unwarranted, as one cannot study neural circuits and genetics without considering experience., Conclusion: The study of maltreated children has a number of advantages for the RDoC project, including the following: study of a subset of patients who are often not responsive to standard interventions; examination of a relatively homogenous sample with onset of psychopathology proposed to be associated with stress-related mechanisms; and well-established, relevant animal models to facilitate translational research., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the extent to which playing a musical instrument is associated with cortical thickness development among healthy youths., Method: Participants were part of the National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development. This study followed a longitudinal design such that participants underwent MRI scanning and behavioral testing on up to 3 separate visits, occurring at 2-year intervals. MRI, IQ, and music training data were available for 232 youths (334 scans), ranging from 6 to 18 years of age. Cortical thickness was regressed against the number of years that each youth had played a musical instrument. Next, thickness was regressed against an "Age × Years of Playing" interaction term. Age, gender, total brain volume, and scanner were controlled for in analyses. Participant ID was entered as a random effect to account for within-person dependence. False discovery rate correction was applied (p ≤ .05)., Results: There was no association between thickness and years playing a musical instrument. The "Age × Years of Playing" interaction was associated with thickness in motor, premotor, and supplementary motor cortices, as well as prefrontal and parietal cortices. Follow-up analysis revealed that music training was associated with an increased rate of thickness maturation. Results were largely unchanged when IQ and handedness were included as covariates., Conclusion: Playing a musical instrument was associated with more rapid cortical thickness maturation within areas implicated in motor planning and coordination, visuospatial ability, and emotion and impulse regulation. However, given the quasi-experimental nature of this study, we cannot rule out the influence of confounding variables., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Clinically, attention-deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity, impulsivity, and inattention and is among the most common childhood disorders. These same traits that define ADHD are variable in the general population, and the clinical diagnosis may represent the extreme end of a continuous distribution of inattentive and hyperactive behaviors. This hypothesis can be tested by assessing the predictive value of polygenic risk scores derived from a discovery sample of ADHD patients in a target sample from the general population with continuous scores of inattention and hyperactivity. In addition, the genetic overlap between ADHD and continuous ADHD scores can be tested across rater and age., Method: The Psychiatric Genomics Consortium has performed the largest genome-wide analysis (GWA) study of ADHD so far, including 5,621 clinical patients and 13,589 controls. The effects sizes of single nucleotide polymorphisms (SNPs) estimated in this meta-analysis were used to obtain individual polygenic risk scores in an independent population-based cohort of 2,437 children from the Netherlands Twin Register. The variance explained in Attention Problems (AP) scale scores by the polygenic risk scores was estimated by linear mixed modeling., Results: The ADHD polygenic risk scores significantly predicted both parent and teacher ratings of AP in preschool- and school-aged children., Conclusion: These results indicate genetic overlap between a diagnosis of ADHD and AP scale scores across raters and age groups and provides evidence for a dimensional model of ADHD. Future GWA studies on ADHD can likely benefit from the inclusion of population-based cohorts and the analysis of continuous scores., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL)., Method: First, genome-wide association (GWA) results were used for density estimation and genome-wide complex trait analysis (GCTA) to calculate the variance explained by all SNPs. Next, a fixed-effect inverse variance meta-analysis of the 3 GWA analyses was carried out. Finally, the overlap in results with prior GWA studies of childhood and adulthood psychiatric disorders and treatment responses was tested by examining whether SNPs associated with these traits jointly showed a significant signal for INT., Results: Genome-wide SNPs explained 13% to 43% of the total variance. This indicates that the genetic architecture of INT mirrors the polygenic model underlying adult psychiatric traits. The meta-analysis did not yield a genome-wide significant signal but was suggestive for the PCSK2 gene located on chromosome 20p12.1. SNPs associated with other psychiatric disorders appeared to be enriched for signals with INT (λ = 1.26, p < .03)., Conclusion: Our study provides evidence that INT is influenced by many common genetic variants, each with a very small effect, and that, even as early as age 3, genetic variants influencing INT overlap with variants that play a role in childhood and adulthood psychiatric disorders., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine whether epigenetic markers predict dimensional ratings of depression in maltreated children., Method: A genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 healthy nontraumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible., Results: Methylation in 3 genes emerged as genome-wide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (ID3); Glutamate Receptor, Ionotropic N-methyl-D-aspartate (NMDA) 1 (GRIN1); and Tubulin Polymerization Promoting Protein (TPPP) (p < 5.0 × 10(-7), all analyses). These genes are all biologically relevant with ID3 involved in the stress response, GRIN1 involved in neural plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different β values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5)., Conclusions: This study suggests that epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. The study adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. Although epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Children with co-occurring internalizing and externalizing problems have higher levels of impairment and worse outcomes later in life, but it is unclear whether these children can be distinguished validly from children who have problems in a single domain. We used a person-centered statistical approach to examine whether a group of children with co-occurring internalizing and externalizing problems can be identified in a general-population sample of young children., Method: This study included a population-based sample of 6,131 children, aged 5 through 7 years. Mothers (92.6%) reported emotional and behavioral problems using the Child Behavior Checklist/1.5-5 (CBCL). A latent profile analysis was performed on the CBCL syndrome scales. Identified classes were compared on early socioeconomic and parental risk factors using multinomial logistic regression., Results: We identified 4 classes, as follows: a class scoring high on all internalizing and externalizing scales (1.8%); a class with internalizing problems (5.3%); a class with externalizing problems and emotional reactivity (7.3%); and a class without problems (85.6%). The first class, with co-occurring problems, was associated with higher levels of maternal and paternal affective symptoms and hostility than the other 3 classes., Conclusions: The class with co-occurring internalizing and externalizing problems appears to be highly similar to the CBCL Dysregulation Profile described in older children. This empirically based dysregulation profile offers a promise to the study of the development of poor self-regulation., (Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Although oppositional defiant disorder (ODD) is usually considered the mildest of the disruptive behavior disorders, it is a key factor in predicting young adult anxiety and depression and is distinguishable from normal childhood behavior. In an effort to understand possible subsets of oppositional defiant behavior (ODB) that may differentially predict outcome, we used latent class analysis of mother report on the Conners' Parent Rating Scales Revised Short Forms (CPRS-R:S)., Method: Data were obtained from mother report for Dutch twins (7 years old, n = 7,597; 10 years old, n = 6,548; and 12 years old, n = 5,717) from the Netherlands Twin Registry. Samples partially overlapped at ages 7 and 10 years (19% overlapping) and at ages 10 and 12 years (30% overlapping), but not at ages 7 and 12 years. Oppositional defiant behavior was measured using the six-item Oppositional subscale of the CPRS-R:S. Multilevel LCA with robust standard error estimates was performed using the Latent Gold program to control for twin-twin dependence in the data. Class assignment across ages was determined and an estimate of heritability for each class was calculated. Comparisons with maternal report Child Behavior Checklist (CBCL) scores were examined using linear mixed models at each age, corrected for multiple comparisons., Results: The LCA identified an optimal solution of four classes across age groups. Class 1 was associated with no or low symptom endorsement (69-75% of the children); class 2 was characterized by defiance (11-12%); class 3 was characterized by irritability (9-11%); and class 4 was associated with elevated scores on all symptoms (5-8%). Odds ratios for twins being in the same class at each successive age point were higher within classes across ages than between classes. Heritability within the two "intermediate" classes was nearly as high as for the class with all symptoms, except for boys at age 12. Children in the Irritable class were more likely to have mood symptoms on the CBCL scales than children in the Defiant class but demonstrated similar scores on aggression and externalizing scales. Children in the All Symptoms class were higher in both internalizing and externalizing scales and subscales., Conclusions: The LCA indicates four distinct latent classes of oppositional defiant behavior, in which the distinguishing feature between the two intermediate classes (classes 2 and 3) is the level of irritability and defiance. Implications for the longitudinal course of these symptoms, association with other disorders, and genetics are discussed., (Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: First, we give an overview of child psychiatric research in the Generation R Study, a population-based cohort from fetal life forward. Second, we examine within Generation R whether the functional polymorphism (5-HTTLPR) in the promoter of the serotonin transporter gene interacts with prenatal maternal chronic difficulties, prenatal maternal anxiety or postnatal maternal anxiety to influence child emotional development., Method: A total of 2,136 northern European children were genotyped for 5-HTTLPR and rs25531. Mothers reported chronic difficulties and anxiety symptoms at 20 weeks' pregnancy and when the child was 3 years old. Child emotion recognition was observed at 3 years, and child emotional problems were assessed with the CBCL/1½-5 at 5 years., Results: There were consistent main effects of maternal difficulties and anxiety on child emotional problems, but no main effect of 5-HTTLPR. Moreover, children with the s allele were at increased risk for emotional problems if their mothers reported prenatal anxiety symptoms (β = 2.02, p < .001) or postnatal anxiety symptoms (β = 1.64, p < 0.001). Also, in children of mothers with prenatal anxiety symptoms, the s allele was associated with less accurate emotion-matching (β = -0.11, p = .004)., Conclusions: This population-based study shows that vulnerability due to 5-HTTLPR is not specific for certain adverse exposures or severe events, but suggests that the small effects of gene-environment interaction on emotional development become manifest early in life., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Children with attention-deficit/hyperactivity disorder (ADHD) have delayed cortical maturation, evidenced by regionally specific slower cortical thinning. However, the relationship between cortical maturation and attention capacities in typically developing children is unknown. This study examines cortical thickness correlates of inattention symptoms in a large sample of healthy children., Method: Data from 357 healthy subjects (6.0-18.4 years of age) were obtained from the NIH MRI Study of Normal Brain Development. In cross-sectional analysis (first visit, n = 257), Child Behavior Checklist Attention Problems (AP) scores were linearly regressed against cortical thickness, controlling for age, gender, total brain volume, and site. For longitudinal data (up to three visits, n = 357/672 scans), similar analyses were performed using mixed-effects linear regressions. Interactions of AP with age and gender were tested., Results: A cross-sectional "AP by age" interaction was found in bilateral orbito-frontal cortex, right inferior frontal cortex, bilateral ventromedial prefrontal cortex, bilateral dorsolateral prefrontal cortex, and several additional attention network regions. The interaction was due to negative associations between AP and thickness in younger subjects (6-10 years of age) that gradually disappeared over time secondary to slower cortical thinning. Similar trends were present in longitudinal analyses., Conclusions: Higher AP scores were associated with thinner cortex at baseline and slower cortical thinning with aging in multiple areas involved in attention processes. Similar patterns have been identified in ADHD, suggesting a dimensional component to the link between attention and cortical maturation. The identified association between cortical maturation and attention in healthy development will help to inform studies of neuroimaging biomarkers of ADHD., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To test for empirically defined temperament phenotypes and to investigate their associations with psychopathology and wellness., Method: The sample included 447 children (259 boys, 188 girls; mean age 11.0 years) recruited for a family study in the northeastern United States. Temperament was measured with the Juvenile Temperament and Character Inventory, and indicators of wellness and psychopathology were assessed with the Child Behavior Checklist from both parents and the Teacher Report Form. Latent profiles analysis was performed with the resulting class membership serving as the dependent variables for multinomial regression analyses., Results: Latent profiles analysis identified three classes as the best fitting solution consisting of a moderate class that had average levels of all four traits, a steady class that had low novelty seeking and high persistence and a disengaged class that had higher novelty seeking and harm avoidance but lower reward dependence and persistence. Regressions demonstrated strong links between the steady class, higher functioning, and lower levels of psychopathology, whereas the disengaged class showed the opposite associations. These findings held across informants of psychopathology and wellness., Conclusions: Profile analyses of temperament may be illuminative in identifying children with similar constellations of traits across many dimensions. Membership in these groups appears to be strongly related to both positive and negative outcomes.