Understanding the Covariation Among Childhood Externalizing Symptoms: Genetic and Environmental Influences on Conduct Disorder,Attention Deficit Hyperactivity Disorder,and Oppositional Defiant Disorder Symptoms

Conduct disorder (CD), attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD) are common childhood externalizing disorders that frequently co-occur. However, the causes of their comorbidity are not well understood. To address that question, we analyzed data from > 600 Finnish twin pairs, who completed standardized interviews at age 14. Behavior genetic methods were used to examine how genetic/environmental factors contribute to each disorders symptoms and to their covariation. We found significant genetic effects on each disorder with only modest evidence of shared environmental influences. Our data suggest the comorbidity among CD, ADHD, and ODD is primarily explained by shared genetic influences; however, each disorder was also under unique genetic influence, supporting the distinction of each disorder.     

Reward and Punishment Sensitivity in Children with ADHD: Validating the Sensitivity to Punishment and Sensitivity to Reward Questionnaire for Children (SPSRQ-C)

This study validates the Sensitivity to Punishment and Sensitivity to Reward Questionnaire for children (SPSRQ-C), using a Dutch sample of 1234 children between 6–13 years old. Factor analysis determined that a 4-factor and a 5-factor solution were best fitting, explaining 41% and 50% of the variance respectively. The 4-factor model was highly similar to the original SPSRQ factors found in adults (Punishment Sensitivity, Reward Responsivity, Impulsivity/Fun-Seeking, and Drive). The 5-factor model was similar to the 4-factor model, with the exception of a subdivision of the Punishment Sensitivity factor into a factor with ‘social-fear’ items and a factor with ‘anxiety’ items. To determine external validity, scores of three groups of children with attention deficit hyperactivity disorder (ADHD) were compared on the EFA models: ADHD-only (n = 34), ADHD and autism spectrum disorder (ADHD+ASD; n = 22), ADHD and oppositional defiant disorder (ADHD+ODD; n = 22). All ADHD groups scored higher than typical controls on Reward Responsivity and on the ‘anxiety’ factor (n = 75). The ADHD-only and ADHD+ODD group scored higher than other groups on Impulsivity/Fun-Seeking and Drive, while the ADHD+ASD group scored higher on Punishment Sensitivity. The findings emphasize the value of the SPSRQ-C to quickly and reliably assess a child’s sensitivity to reinforcement, with the aim to provide individually-tailored behavioral interventions that utilize reward and reprimands.     

Exploring the Relationship Between Autistic-Like Traits and ADHD Behaviors in Early Childhood: Findings from a Community Twin Study of 2-Year-Olds

Behaviors characteristic of autism and ADHD emerge in early childhood, yet research investigating their comorbidity has focused on older children. This study aimed to explore the nature of the relationship between autistic-like traits and ADHD behaviors in a community sample of 2-year-olds. Twins from the Boston University Twin Project (N = 312 pairs) were assessed by their parents on autistic-like traits and ADHD behaviors using the Childhood Behavior Checklist. Phenotypic analyses showed that after controlling for general cognitive ability and socioeconomic status, autistic-like traits (total scale as well as social and nonsocial subscales) correlated positively with ADHD behaviors (r = 0.23–0.26). Structural equation model-fitting analyses revealed that there were modest shared genetic influences between ADHD- and autistic traits (genetic correlation = 0.27) as well as some common environmental influences explaining their covariation. Implications for identifying shared biological pathways underlying autistic-like traits and ADHD behaviors are discussed.     

Genetic and Environmental Contributions to Common Psychopathologies of Childhood and Adolescence: A Study of Twins and Their Siblings

We report findings based on analyses of self-reports of six common adolescent psychopathologies (attention deficit/hyperactivity disorder, ADHD; conduct disorder, CD; oppositional defiant disorder, ODD; generalized anxiety disorder, GAD; separation anxiety disorder, SAD; and major depressive disorder, MDD) in a sample of 1,162 male and female adolescent (12–19 years) twin pairs and 426 siblings. Prevalence statistics for past year and lifetime reports confirm differences between genders for CD, GAD, SAD, and MDD, and a lack of differences between twins and their non-twin siblings. Biometrical modeling was conducted to ascertain the relative influences of genes, and shared and non-shared environments contributing to these disorders. A more robust estimate of these parameters was obtained by including non-twin siblings. Age-specific thresholds were integrated into the analyses to appropriately model the developmental patterns of behavior. We found evidence for both genetic and non-shared environmental influences for all disorders. Shared environmental influences also seem to be important for MDD and lifetime GAD.     

Etiology of Inattention and Hyperactivity/Impulsivity in a Community Sample of Twins with Learning Difficulties

A community sample of 373 8 to 18 year-old twin pairs in which at least one twin in each pair exhibited a history of learning difficulties was utilized to examine the etiology of inattention and hyperactivity/impulsivity (hyp/imp). Symptoms of attention-deficit/hyperactivity disorder (ADHD) were assessed by the DSM-III Diagnostic Interview for Children and Adolescents. Inattention and hyp/imp composite scores were created based on results of a factor analysis. Results indicated that extreme ADHD scores were almost entirely attributable to genetic influences across several increasingly extreme diagnostic cutoff scores. Extreme inattention scores were also highly heritable whether or not the proband exhibited extreme hyp/imp. In contrast, the heritability of extreme hyp/imp increased as a linear function of the number of inattention symptoms exhibited by the proband. This finding suggests that extreme hyp/imp may be attributable to different etiological influences in individuals with and without extreme inattention. If this result can be replicated in other samples, it would provide evidence that the hyp/imp symptoms exhibited by individuals with Combined Type ADHD and Predominantly Hyp/Imp Type ADHD may be attributable to different etiological influences.     

Sex differences in genetic and environmental influences on DSM-III-R attention-deficit/hyperactivity disorder

Approximately 5% of children are affected by attention-deficit/hyperactivity disorder (ADHD), and more boys are affected than girls. This study examined the magnitude of genetic and environmental influences on ADHD and several questions regarding sex differences in its prevalence and liability. The participants were 2,391 twin and sibling pairs from Australia, ages 3-18. ADHD symptoms in the general population were highly heritable (h2 = .85-.90), as were deviant ADHD scores in the selected population. The magnitude of familial influences was similar for boys and girls, although there were shared environmental influences on ADHD in girls but not boys and dominance genetic influences on ADHD in boys but not girls. Specific genetic and environmental influences were highly similar for boys and girls. Evidence supported the polygenic multiple threshold model rather than the constitutional variability model of sex differences in ADHD.     

Gene-Environment Interactions in ADHD: The Roles of SES and Chaos

Although attention-deficit/hyperactivity disorder (ADHD) is highly heritable, emerging evidence suggests symptoms are associated with interactions between genes and the environment (GxE) during development. This study tested whether heritability of ADHD symptoms is moderated by two environmental factors: socioeconomic status (SES) and chaos (household disorganisation). A population sample of 520 twin pairs (N = 1040, 52.3% female) from 6 to 15 years completed measures of behavior and home environment. Structural equation modelling was then used to test whether environmental factors were associated with a change in the extent to which genes explain variability in ADHD symptoms. Neither chaos nor SES moderated heritability, with consistent contributions from both genes and environment indicated across socioeconomic strata and levels of chaos. This finding contrasts with those of previous research, underlining the need to replicate results in the emerging field of GxE research across different populations and statistical methods. Robust findings may assist in developing targeted interventions for genetically vulnerable individuals.     

Association of Positive and Negative Parenting Behavior with Childhood ADHD: Interactions with Offspring Monoamine Oxidase A (MAO-A) Genotype

Relatively little is known about the potential interplay between genetic and environmental influences on attention-deficit/hyperactivity disorder (ADHD), including gene-environment interaction (G×E). There is evidence that parenting behavior interacts with offspring genotype in the development of externalizing problems, but studies have largely focused on explicit maltreatment rather than differentiated measures of parenting behavior, including positive and negative parenting. We tested the interactive effects of the 30-base pair variable number tandem repeat (VNTR) polymorphism of the monoamine oxidase A gene (MAO-A) with positive and negative parenting behavior on parent- and teacher ratings of inattention and hyperactivity symptoms among 150 6–9 year-old boys with and without ADHD. Negative parenting predicted parent and teacher ratings of inattention symptoms, but only among boys with high-activity MAO-A genotype. MAO-A genotype did not moderate the association of positive parenting and parent- and teacher ratings of ADHD. We discuss the potential role of interactive exchanges between parenting behavior and child genotype in the development and persistence of ADHD and related behavior problems.     

Genetic overlap between ADHD symptoms and EEG theta power

Biological markers that are grounded in neuroscience may facilitate understanding of the pathophysiology of complex psychiatric disorders. One of the most consistent and robust neural abnormalities in attention deficit hyperactivity disorder (ADHD) is increased EEG power in the theta band at rest (4–8 Hz). The present study used a twin design to estimate the extent of genetic overlap between increased theta power and risk for ADHD in order to validate theta power as a marker of genetic risk for ADHD. At rest, EEG was measured in 30 monozygotic and dizygotic adolescent twin pairs concordant or discordant for high ADHD symptom scores and 37 monozygotic and dizygotic control twin pairs with low ADHD symptom scores. Structural equation modelling was used to estimate the heritability of theta power and partition the genetic and environmental contributions to the overlap between ADHD and theta power. A significant phenotypic correlation between ADHD symptoms and elevated theta power was found. Theta power demonstrated moderate to high heritability estimates (0.77) and moderate genetic correlations with ADHD (0.35) suggesting shared genetic influences. Increased theta power is a candidate biological marker of genetic risk for ADHD, which warrants further investigation of the neurobiological mechanisms that underlie the genetic relationship.     

Comparing Four Methods of Integrating Parent and Teacher Symptom Ratings of Attention-deficit/hyperactivity Disorder (ADHD)

Although parents and teachers are valid informants in the assessment of childhood attention-deficit/hyperactivity disorder (ADHD), there is relatively little systematic research on how these ratings should be optimally combined. We compared four methods of ADHD assessment to determine how well they identified impaired children: (1) parent only, (2) teacher only, (3) parent or teacher (‘or rule’), and (4) parent and teacher (‘and rule’). We obtained parent and teacher ratings of ADHD from the Disruptive Behavior Disorder Rating Scale on 232 5- to 10-year-old children (69% male; 47% Caucasian) with (n = 121) and without (n = 111) ADHD. We used receiver operating characteristic curves (ROC) and seemingly unrelated regression analyses (SUR) to evaluate how accurately each method identified categorically- and dimensionally-defined measures of functional impairment. Parent ratings of ADHD optimally identified globally impaired children based on categorical and dimensional measures. However, teacher ratings of ADHD most accurately identified children who were negatively regarded by peers using categorical, but not dimensional, measures. No ADHD assessment method effectively identified children with academic difficulties. Although multiple informants are valuable in the assessment of ADHD, no single method was consistently superior in identifying impaired children across domains. We consider alternative assessment strategies in ADHD as well as other potential factors that may contribute to modest agreement among informants.     

In the Face of Uncertainty: A Twin Study of Ambiguous Information,Anxiety and Depression in Children

Anxiety and depression share genetic influences, and have been associated with similar cognitive biases. Psychological theories of anxiety and depression highlight threat interpretations of ambiguity. Little is known about whether genes influence cognitive style, or its links to symptoms. We assessed ambiguous word and scenario interpretations, anxiety and depression symptoms in 300 8-year-old twin pairs. There were significant correlations between both negative interpretations of ambiguous words and scenarios and depression symptoms after controlling for anxiety symptoms (r = .13 and .31, respectively), but no significant correlations with anxiety independent of depression. Genetic effects ranged from 16% for depression to 30% for ambiguous word interpretations. Non-shared environmental influences were large (68–70%). Both genetic and environmental influences contributed to the association between depression and ambiguous scenario interpretations. These findings support psychological theories, which emphasise the role of environmental stress both on the development of threat interpretations and on their links with symptoms. The data also support a role for genetic influence on threat interpretations, which may mediate responses to stress.     

A Twin Study of the Relationships among Inattention, Hyperactivity/Impulsivity and Sluggish Cognitive Tempo Problems

We investigated the etiological relationships between the three ADHD dimensions of Inattentive Problems (INP), Hyperactivity-Impulsivity Problems (HIP) and Sluggish Cognitive Tempo (SCT) as measured by the CBCL 6–18 questionnaire. Multivariate models were applied to 398 twin pairs (374 boys and 422 girls) aged 8 to 17 years (M?=?13.06, SD?=?2.59) belonging to the population-based Italian Twin Registry. The INP, HIP and SCT problem scores were moderately-to-substantially (range 0.29–0.47) intercorrelated. The best fitting model showed that these 3 dimensions are correlated both at the genetic (correlations’ range: 0.65–0.83) and the environmental (correlations: 0.29 and 0.44) levels, but they are also distinct. While SCT showed moderate heritability and large non-shared environmental influences, variance for both INP and HIP was substantially explained by genetic influences. We also found evidence of negative sibling interaction for INP, implying that a given behavior in one twin leads to an opposite behavior in the co-twin. Our results support at the etiological level the findings of previous psychometric and longitudinal studies of ADHD, which yielded evidence of the 3 distinct—albeit correlated—problem dimensions of inattentiveness, hyperactivity-impulsivity, and sluggish cognitive tempo.     

The Stigmatising Implications of Presenting Schizophrenia as a Genetic Disease

This study aimed to investigate the hypothesis that belief in a genetic aetiology of schizophrenia will increase the stigma associated with the disorder. Levels of five potentially stigmatising attitudes were compared in two groups of participants who had read a vignette describing an individual who has schizophrenia. In one group the disorder was explained as being caused by ‘genetic’ factors, and in the other by ‘environmental’ factors. This study found that three of the five potentially stigmatising attitudes measured were increased when participants read a vignette with a genetic causation rather than an environmental causation. Firstly, genetic attributions increased levels of associative stigma towards close relatives (p < 0.001). Secondly, participants viewed recovery as less likely when genetic factors were implicated as causative (p < 0.001). Finally, there was also an increased perception of the character’s “dangerousness” when the condition was explained by genetic factors (p < 0.05). Contrary to previous research was the finding that perceived aetiology had no effect on participant’s desire for social distance from an affected individual. Neither did perceived aetiology influence beliefs about moral accountability. The implications of these findings suggest that genetic counsellors and other health professionals, who are providing genetic information to those affected by schizophrenia should be aware of the possibility that a genetic explanation of schizophrenia could increase potentially stigmatising attitudes towards their clients and their clients’ families. It is also possible that individuals with a diagnosis of schizophrenia may themselves form deterministic interpretations of the genetic information they receive and subsequently be less likely to adopt behavioural advice or adhere to treatment. Counsellors and health professionals should strive to present information in a balanced manner, ensuring recipients understand the multi-factorial causes of the disease.     

Etiological Distinctions between Aggressive and Non-aggressive Antisocial Behavior: Results from a Nuclear Twin Family Model

A recent meta-analysis of 103 studies Burt (Clinical Psychology Review, 29:163-178, 2009a) highlighted the presence of etiological distinctions between aggressive (AGG) and non-aggressive rule-breaking (RB) dimensions of antisocial behavior, such that AGG was more heritable than was RB, whereas RB was more influenced by the shared environment. Unfortunately, behavioral genetic research on antisocial behavior to date (and thus, the research upon which the meta-analysis was based) has relied almost exclusively on the classical twin model. This reliance is problematic, as the strict assumptions that undergird this model (e.g., shared environmental and dominant genetic influences are not present simultaneously; there is no assortative mating) can have significant consequences on heritability estimates when they are violated. The nuclear twin family model, by contrast, allows researchers to relax and statistically evaluate many of the assumptions of the classical twin design by incorporating parental self-report data along with the more standard twin data. The goal of the current study was thus to evaluate whether prior findings of etiological distinctions between AGG and RB persisted when using the nuclear twin family model. We examined a sample of 312 child twin families from the Michigan State University Twin Registry. Results strongly supported prior findings of etiological distinctions between AGG and RB, such that broad genetic influences were observed to be particularly important to AGG whereas shared environmental influences contributed only to RB. Nevertheless, the current findings also implied that additive genetic influences on antisocial behavior may be overestimated when using the classical twin design.     

Genetic Support for the Dual Nature of Attention Deficit Hyperactivity Disorder: Substantial Genetic Overlap Between the Inattentive and Hyperactive–impulsive Components

Objective Attention deficit hyperactivity disorder (ADHD) is a common, complex and highly heritable disorder, characterised by inattentive, impulsive and overactive behaviour. Evidence for the heritability of ADHD measures in twin population samples has come from the analysis of total scores that combine inattentive and hyperactive–impulsive symptoms subscales. This study investigated, in a community sample, the aetiology of ADHD-like traits and the aetiological overlap between the two dimensions that define the ADHD disorder. Materials and Methods Parents of 6,222 approximately 8-year-old twin pairs from the Twins Early Development Study (TEDS) population sample completed the two subscales of the Conners’ 18-item DSMIV checklist, a screening instrument for ADHD symptoms. Results Both subscales were highly heritable (hyperactive–impulsive: 88%; inattentive: 79%). Bivariate genetic modelling indicated substantial genetic overlap between the two components; however, there were significant independent genetic effects. Conclusions These findings suggest that many genes associated with the hyperactivity–impulsivity dimension will also be associated with the inattentive dimension but that there is significant genetic heterogeneity as well. These results provide genetic support for combining the two behavioural dimensions that define ADHD, but also suggest that some symptom-specific genes will also be identified. Correspondence and reprint requests to Gráinne McLoughlin, SGDP Centre, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, Tel: +44(0) 207-848-5261; Email: g.mcloughlin@iop.kcl.ac.uk.     

Association of <Emphasis Type="Italic">ADAM10</Emphasis> and <Emphasis Type="Italic">CAMK2A</Emphasis> Polymorphisms with Conduct Disorder: Evidence from Family-Based Studies

Twin and family studies have shown that genetic factors play a role in the development of conduct disorder (CD). The purpose of this study was to identify genetic variants associated with CD using a family-based association study. We used 4,720 single nucleotide polymorphisms (SNPs) from the Illumina Panel and 11,120 SNPs from the Affymetrix 10K GeneChips genotyped in 155 Caucasian nuclear families from Genetic Analysis Workshop (GAW) 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). 20 SNPs had suggestive associations with CD (p < 10⁻³), nine of which were located in known genes, including ADAM10 (rs383902, p = 0.00036) and CAMK2A (rs2053053, p = 0.00098). Our results were verified using the International Multi-Center ADHD Genetics Project (IMAGE) dataset. In conclusion, we identified several loci associated with CD. Especially, the two genes (ADAM10 and CAMK2A) have been reported to be associated with Alzheimer’s disease, bipolar disorder and depression. These findings may serve as a resource for replication in other populations.     

多动症的遗传学研究概述

多动症多始于儿童期,并能持续至成年期。传统的家庭、双生子和养子女研究表明,多动症是受遗传影响的。双生子研究现在被用来定义多动症表型,分析性别差异,测试基因对持续性和共病的影响,以及研究遗传与环境的互动。多动症的分子遗传学研究集中在功能候选基因的关联分析上。多动症与DRD4和DRD5的关系比较一致。最新的研究也显示COMT的影响。关联分析（linkage analysis）显示这些单个基因的影响都不大。这个领域还有待于大规模的“全基因关联”分析。至今为止的证据显示,研究基因-表型关联以及基因与环境互动对多动症的影响将日趋重要     

The Dopamine Receptor D4 Gene (<Emphasis Type="Italic">DRD4</Emphasis>) Moderates Family Environmental Effects on ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G x E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G x E design, we examined whether the DRD4 promoter 120-bp tandem repeat polymorphism, previously associated with ADHD, moderated the effects of inconsistent parenting and marital conflict on ADHD or Oppositional-Defiant Disorder (ODD). Participants were 548 children with ADHD and non-ADHD comparison children and their parents. Homozygosity for the DRD4 promoter 120-bp tandem repeat insertion allele increased vulnerability for ADHD and ODD only in the presence of inconsistent parenting and appeared to increase susceptibility to the influence of increased child self-blame for marital conflict on ADHD inattention. DRD4 genotypes may interact with these proximal family environmental risk factors by increasing the individual’s responsivity to environmental contingencies.     

Differential Genetic and Environmental Influences on Reactive and Proactive Aggression in Children

While significant heritability for childhood aggression has been claimed, it is not known whether there are differential genetic and environmental contributions to proactive and reactive forms of aggression in children. This study quantifies genetic and environmental contributions to these two forms of aggression in an ethnically diverse urban sample of 9–10 year old twins (N = 1219), and compares results across different informants (child self-report, mother, and teacher ratings) using the Reactive–Proactive Aggression Questionnaire (RPQ). Confirmatory factor analysis of RPQ items indicated a significant and strong fit for a two-factor proactive–reactive model which was significantly superior to a one-factor model and which replicated across gender as well as the three informant sources. Males scored significantly higher than females on both self-report reactive and proactive aggression, findings that replicated on mother and teacher versions of the RPQ. Asian–Americans scored lower than most ethnic groups on reactive aggression yet were equivalent to Caucasians on proactive aggression. African–Americans scored higher than other ethnic groups on all measures of aggression except caregiver reports. Heritable influences were found for both forms of aggression across informants, but while boys’ self-reports revealed genetic influences on proactive (50%) and reactive (38%) aggression, shared and non-shared environmental influences almost entirely accounted for girls’ self-report reactive and proactive aggression. Although genetic correlations between reactive and proactive aggression were significant across informants, there was evidence that the genetic correlation was less than unity in boys self reported aggression, indicating that genetic factors differ for proactive and reactive aggression. These findings provide the first evidence for varying genetic and environmental etiologies for reactive and proactive aggression across gender, and provide additional support for distinction between these two forms of aggression.     

Exploring how symptoms of attention-deficit/hyperactivity disorder are related to reading and mathematics performance: general genes, general environments

Children with attention-deficit/hyperactivity disorder (ADHD) tend to perform more poorly on tests of reading and mathematical performance than their typical peers. Quantitative genetic analyses allow for a better understanding of the etiology of ADHD and reading and mathematics outcomes, by examining their common and unique genetic and environmental influences. Analyses were conducted on a sample 271 pairs of 10-year-old monozygotic and dizygotic twins drawn from the Western Reserve Reading and Mathematics Project. In general, the results suggested that the associations among ADHD symptoms, reading outcomes, and math outcomes were influenced by both general genetic and general shared-environment factors. The analyses also suggested significant independent genetic effects for ADHD symptoms. The results imply that differing etiological factors underlie the relationships among ADHD and reading and mathematics performance. It appears that both genetic and common family or school environments link ADHD with academic performance.