Comorbid ADHD and mental health disorders: are these children more likely to develop reading disorders?

While attention-deficit/hyperactivity disorder (ADHD) has been associated with both internalizing and externalizing childhood behaviour disorders, the specific relationship of these comorbid disorders to ADHD and reading problems is less well defined. The present study analysed data from the Australian Twin ADHD Project, which utilized DSM-IV-based ratings of ADHD, separation anxiety disorder, generalized anxiety disorder, depression, conduct disorder, and oppositional defiant disorder for twins and siblings aged 6 to 18 years. While differences between children with and without ADHD were demonstrated for those with separation anxiety disorder, generalized anxiety disorder, depression, conduct disorder, oppositional defiant disorder and a reading disorder, for all age groups, regression analysis of ADHD diagnostic subtypes by age and reading disorder showed that only generalized anxiety disorder remained significant after controlling for ADHD subtypes. Analysis of the mean reading disorder scores in children with and without ADHD showed that children with conduct disorder had significantly more reading problems, as did children with multiple comorbid disorders. In summary, both age and ADHD diagnosis were associated with variations in these comorbid disorders, and multiple comorbid disorders were associated with greater reading impairment.

Phenotype refinement for comorbid attention deficit hyperactivity disorder and reading disability.

Comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and reading disability (RD) is common; however, the heritability of this comorbidity is not well understood. This may be due to the complexity and heterogeneity of ADHD and RD phenotypes. Using alternative ADHD-RD sub-phenotypes instead of those arising from the DSM-IV may lead to greater success in the search for comorbid ADHD-RD susceptibility genes. Therefore, this study aims to refine ADHD-RD phenotypes into homogenous informative sub-phenotypes using latent class analysis (LCA). LCA was performed on 2,610 Australian twin families (6,535 individuals) in order to generate probabilistic genetically distinct classes that define ADHD-RD subtypes, including comorbidity, based on related symptom clusters. The LCA separated the phenotypes for ADHD and RD into nine classes. One class was unaffected; three classes demonstrated the three DSM-IV subtypes of ADHD, three subtypes showed different severities of RD, and two classes expressed a combination of RD and ADHD subtypes. LCA proved effective in refining the phenotypes of ADHD alone, RD alone, and ADHD-RD comorbidity, and its ability to classify them into homogenous groups based on clusters of symptoms, suggesting that the latent classes may be robust enough to use in molecular genetic studies.

Motor disorder and anxious and depressive symptomatology: a monozygotic co-twin control approach.

The aim of this study was to investigate the relationship between poor motor ability and anxious and depressive symptomatology in child and adolescent monozygotic twins. The co-twin control design was used to explore these mental health issues in MZ twins concordant and discordant for a motor disorder, and controls. This methodology offers the unique opportunity to control for genetic effects and shared environmental influences, and permits the investigation of non-shared environmental influences. The Developmental Coordination Disorder Questionnaire was used to identify 23 sets of twins discordant for a motor disorder, 23 sets concordant for a motor disorder, and 773 sets of twins with no motor disorder from a total sample of 2122 Australian sets of twins. The Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour questionnaire was used to exclude participants with high Attention Deficit Hyperactivity Disorder symptomatology. Anxious and depressive symptomatology were assessed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) based questionnaires on Generalised Anxiety Disorder and Sad Affect. Results indicated significantly higher levels of anxious and depressive symptomatology in twins with a motor disorder in discordant pairs compared to their co-twins without a motor disorder, and controls. There were significantly higher levels of anxious symptomatology in twins with a motor disorder in discordant sets than in sets of twins concordant for a motor disorder. There were significantly higher levels of anxious symptomatology in concordant twins than in controls. Implications of these findings are discussed with emphasis on understanding and recognising the relationship between a motor disorder and anxious and depressive symptomatology in clinical practice for children and adolescents with these disorders.

An examination of the relationship between movement problems and four common developmental disorders.

It has been well recognized since the days of "minimal brain dysfunction" (Clements, 1966) that various developmental disorders have a shared aetiology. Poor motor coordination has been implicated as one of the factors in these relationships. This study examines the different patterns in symptomatology of five developmental disorders, namely developmental coordination disorder (DCD), attention-deficit/hyperactivity disorder (ADHD), reading disorder (RD), oppositional defiant disorder (ODD), and conduct disorder (CD) in order to build on the genetic work from Martin, Levy, Piek, and Hay (2006) and Martin, Piek, and Hay (2006) examining the overlap of these disorders. Latent class analysis was used on questionnaire data from 1304 families from the Australian twin ADHD project (ATAP) to examine the patterns of comorbidity of the five disorders. We confirmed and added detail to the shared symptoms between DCD, ADHD, RD, and ODD, but found no links between CD symptoms and any other disorders. Despite the close link previously identified with ODD and CD, this finding suggests a different aetiology for CD.

Genetic overlap between measures of hyperactivity/inattention and mood in children and adolescents.

OBJECTIVE: Evidence suggests that there is substantial comorbidity between attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder in childhood and adolescence. This study aims to investigate the degree to which etiological factors are shared between the symptoms of these significantly heritable disorders. METHOD: A twin study design was used to determine to what extent the covariation between the traits of ADHD and depression is genetically or environmentally mediated, based on parental reports. A general community sample of 645 twin pairs aged 5 to 17 years from the Cardiff Study of All Wales and North England Twins project took part in the study. Parent-rated measures of hyperactivity/inattention (Abbreviated Conners Hyperactivity subscale) and depression (Short Mood and Feelings Questionnaire). RESULTS: Phenotypes derived from the scales were significantly correlated in both boys and girls. Bivariate structural equation modeling revealed a large overlap in underlying genetic factors (boys, rA = 0.77; girls, rA = 0.67) along with a smaller influence of nonshared environment. CONCLUSIONS: These findings suggest that there are common genes conferring liability to both hyperactive/inattentive and depressive traits in children and adolescents. This has implications for future molecular genetic research into ADHD and major depressive disorder. Additionally, it indicates that the comorbid clinical presentation of these disorders may reflect a common genetic pathway.

An investigation into etiological pathways of DCD and ADHD using a monozygotic twin design.

We previously described a co-twin control design using questionnaire data on monozygotic twins discordant and concordant for developmental coordination disorder (DCD) and attention deficit hyperactivity disorder (ADHD). Our results suggested that DCD and developmental ADHD had different causal pathways, and that second-born twins were at higher risk for oxygen perfusion problems than first-born twins. In the current study we further explored our findings using DNA confirmed zygosity and assessments of 4 female and 10 male sets of monozygotic twins, aged 8 to 17 years, from the first study. Using the McCarron Assessment of Neuromuscular Development (MAND), twice as many second- as first-born twins met criteria for DCD. Second-born twins attained significantly lower scores on 1-minute Apgar, MAND Gross Motor, Bimanual Dexterity and Neuromuscular Development Index. Seven of the nine twins who met criteria for DCD experienced perinatal oxygen perfusion problems. This supported findings in the first study of an association between perinatal oxygen perfusion problems and DCD, and our hypothesis that DCD and cerebral palsy have similar causal pathways. We found similar numbers of males and females discordant for DCD. On telephone interview using the Diagnostic Interview Schedule for Children Parent Interview, the only first-, and all five second-born twins who met criteria for ADHD had an inattentive component - three Inattentive; three Combined. All twins positive for ADHD were male. This adds support to our hypothesis that ADHD symptoms found in some participants may reflect secondary ADHD associated with environmental factors, rather than developmental ADHD.

Attention deficit hyperactivity disorder: a Rasch analysis of the SWAN Rating Scale.

The prevalence of attention-deficit/hyperactivity disorder (ADHD) has been estimated at 3-7% in the population. Children with this disorder are often characterized by symptoms of inattention and/or impulsivity and hyperactivity, which can significantly impact on many aspects of their behaviour and performance. This study investigated the characteristics of the SWAN Rating Scale and its discrimination of ADHD subtypes. This instrument was developed by Swanson and his colleagues and measures attentiveness and hyperactivity on a continuum, from attention problems to positive attention skills, using a seven-point scale of behaviour: "far below average" to "far above average". The Australian Twin Attention-Deficit/Hyperactivity Disorder Study consists of questionnaire data collected from families in 1990/2007. The Rasch model was used to measure the characteristics of items from the SWAN Rating Scale; how well these items discriminated between those with and without ADHD. The prevalence of each subtype was found to be 5.3% for inattentive ADHD, 4.3% for hyperactive ADHD and 4.6% for combined ADHD. A total of 14.2% of the cohort appeared to have ADHD. While the inattentive items appeared to be consistent with each other in their measurement behaviour and response patterns, the hyperactive items were less consistent. Further, the combined subtype appeared to be an entirely different type, with unique features unlike the other two subtypes. Further work is needed to distinguish the diagnostic features of each subtype of ADHD.

Comorbid problems in ADHD: degree of association, shared endophenotypes, and formation of distinct subtypes. Implications for a future DSM.

We aimed to assess which comorbid problems (oppositional defiant behaviors, anxiety, autistic traits, motor coordination problems, and reading problems) were most associated with Attention-Deficit/Hyperactivity Disorder (ADHD); to determine whether these comorbid problems shared executive and motor problems on an endophenotype level with ADHD; and to determine whether executive functioning (EF)-and motor-endophenotypes supported the hypothesis that ADHD with comorbid problems is a qualitatively different phenotype than ADHD without comorbid problems. An EF-and a motor-endophenotype were formed based on nine neuropsychological tasks administered to 816 children from ADHD-and control-families. Additional data on comorbid problems were gathered using questionnaires. Results indicated that oppositional defiant behaviors appeared the most important comorbid problems of ADHD, followed by autistic traits, and than followed by motor coordination problems, anxiety, and reading problems. Both the EF-and motor-endophenotype were correlated and cross-correlated in siblings to autistic traits, motor coordination problems and reading problems, suggesting ADHD and these comorbid problems may possibly share familial/genetic EF and motor deficits. No such results were found for oppositional defiant behaviors and anxiety. ADHD in co-occurrence with comorbid problems may not be best seen as a distinct subtype of ADHD, but further research is warranted.

Neuropsychological measures probably facilitate heritability research of ADHD.

Previous studies, in which cognitive and motor neuropsychological tasks were administered to 816 children from Attention-Deficit/Hyperactivity Disorder (ADHD)- and control-families, showed that various of these measures appeared useful for genetic research in ADHD by forming candidate endophenotypes: underlying, heritable, vulnerability traits that mark an enhanced liability for developing ADHD. The current study extends these findings by showing that six of these ten measures correlate more strongly between siblings than an ADHD composite, suggesting these measures may have a larger heritability than ADHD itself. Significant sibling cross-correlations also suggested that six of ten neuropsychological measures related to similar familial (and heritable) factors as ADHD, suggesting these measures to be useful for ADHD genetic research. An aggregated neuropsychological composite appeared to be the most powerful, since it correlated more strongly between siblings than most individual task measures. These findings suggest heritability research in ADHD will probably be facilitated by including neuropsychological measures.

What are the key directions in the genetics of attention deficit hyperactivity disorder?

PURPOSE OF REVIEW: The aim of this review is to describe the considerable advances in consolidating the empirical evidence on several key topics in the genetics of attention deficit hyperactivity disorder, namely the quantitative genetic studies of the nature of attention deficit hyperactivity disorder and its comorbidities, the molecular genetic studies that show modest but consistent effects of specific genotypes, and the growing recognition of genotype by environment interaction. Such interactions are studied to explain what happens when individuals with a susceptible genotype are exposed to a particular environment. RECENT FINDINGS: There have been a significant number of twin studies that have examined different models of the symptomatology of attention deficit hyperactivity disorder and how these symptoms are reported. Similarly, molecular genetic research is complicated by very different outcome measures, and study across the whole field is made more problematic by genotype by environment interaction effects. One of the most interesting areas of development is that of psychopharmacogenetics. SUMMARY: Two key developments have been integrative models of the genetics of attention deficit hyperactivity disorder and brain structure, which may have implications for future attention deficit hyperactivity disorder subtyping, and collaboration. This is not just within attention deficit hyperactivity disorder as in the IMAGE study, but also across disciplines.

Relationship between endophenotype and phenotype in ADHD.

BACKGROUND: It has been hypothesized that genetic and environmental factors relate to psychiatric disorders through the effect of intermediating, vulnerability traits called endophenotypes. The study had a threefold aim: to examine the predictive validity of an endophenotypic construct for the ADHD diagnosis, to test whether the magnitude of group differences at the endophenotypic and phenotypic level is comparable, and to investigate whether four factors (gender, age, IQ, rater bias) have an effect (moderation or mediation) on the relation between endophenotype and phenotype. METHODS: Ten neurocognitive tasks were administered to 143 children with ADHD, 68 non-affected siblings, and 120 control children (first-borns) and 132 children with ADHD, 78 non-affected siblings, and 113 controls (second-borns) (5 - 19 years). The task measures have been investigated previously for their endophenotypic viability and were combined to one component which was labeled 'the endophenotypic construct': one measure representative of endophenotypic functioning across several domains of functioning. RESULTS: The endophenotypic construct classified children with moderate accuracy (about 50% for each of the three groups). Non-affected children differed as much from controls at the endophenotypic as at the phenotypic level, but affected children displayed a more severe phenotype than endophenotype. Although a potentially moderating effect (age) and several mediating effects (gender, age, IQ) were found affecting the relation between endophenotypic construct and phenotype, none of the effects studied could account for the finding that affected children had a more severe phenotype than endophenotype. CONCLUSION: Endophenotypic functioning is moderately predictive of the ADHD diagnosis, though findings suggest substantial overlap exists between endophenotypic functioning in the groups of affected children, non-affected siblings, and controls. Results suggest other factors may be crucial and aggravate the ADHD symptoms in affected children.

Depressive symptomatology in child and adolescent twins with attention-deficit hyperactivity disorder and/or developmental coordination disorder.

Previous research has demonstrated a link between attention-deficit/hyperactivity disorder (ADHD), developmental coordination disorder (DCD), and depression. The present study utilized a monozygotic (MZ) differences design to investigate differences in depressive symptomatology between MZ twins discordant for ADHD or DCD. This extends previous research as it controls for genetic effects and shared environmental influences and enables the investigation of nonshared environmental influences. In addition, children and adolescents with comorbid ADHD and DCD were compared on their level of depressive symptomatology to those with ADHD only, DCD only, and no ADHD or DCD. The parent-rated Strengths and Weaknesses of ADHD Symptoms and Normal Behavior, Developmental Coordination Disorder Questionnaire, and Sad Affect Scale were used to assess ADHD, DCD, and depressive symptomatology respectively. The results revealed higher levels of depressive symptomatology in MZ twins with ADHD or DCD compared to their nonaffected co-twins. In addition, children and adolescents with comorbid ADHD and DCD demonstrated higher levels of depressive symptomatology compared to those with ADHD only, DCD only, and no ADHD or DCD. The implications of these findings are discussed with emphasis on understanding and recognizing the relationship between ADHD, DCD, and depression in the assessment and intervention for children and adolescents with these disorders.

PKDB: Polycystic Kidney Disease Mutation Database--a gene variant database for autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) arises from mutations in the PKD1 and PKD2 genes. The Polycystic Kidney Disease Mutation Database (PKDB) is an internet-accessible relational database containing comprehensive information about germline and somatic disease-causing variants within these two genes, as well as polymorphisms and variants of indeterminate pathogenicity. The PKDB database structure incorporates an interface between these gene variant data and any associated patient clinical data. An initiative of the Polycystic Kidney Disease Foundation, PKDB is a publicly accessible database that aims to streamline the evaluation of PKD1 and PKD2 gene variants detected in samples from those with ADPKD, as well as to assist ongoing clinical and molecular research in the field. As the accurate reporting of nucleotide variants is essential for ensuring the quality of data within PKDB, a mutation checker has been mounted on the PKDB server allowing contributors to assess the accuracy of their PKD1 and PKD2 variant reports. Researchers and clinicians may submit their PKD1/PKD2 gene variants and any associated deidentified clinical data via standardized downloadable data entry forms accessible through the PKDB site. PKDB has been launched with the full details of PKD1 and PKD2 gene variant reports published in 73 peer-reviewed articles. Through a series of user-friendly advanced search facilities, users are able to query the database as required. The PKDB server is accessible at http://pkdb.mayo.edu.

DCD and ADHD: a genetic study of their shared aetiology.

Previous studies have found that rates of attention deficit hyperactivity disorder (ADHD) and developmental coordination disorder (DCD) are very similar, both being approximately 7% in sample populations [Kadesjö, B., & Gillberg, C. (1999). Developmental coordination disorder in Swedish 7-year-old children. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 820-828; Milberger, S., Faraone, S., Biederman, J., Testa, M., & Tsuang, M. (1996). New phenotype definition of attention deficit hyperactivity disorder in relatives for genetic analyses. American Journal of Medical Genetics, 67, 369-377]. The rate of comorbidity between the two has been found to be close to 50% [Barkley, R. (1990). Attention deficit hyperactivity disorder: A handbook for diagnosis and treatment. New York: Guilford Press]. Investigations into the comorbidity of the disorders points to a shared aetiology between them. The aim of the present investigation was to examine the extent to which the shared aetiology is due to common genetic factors to both disorders. We also investigated whether particular subtypes of each disorder were more linked than others. Mailed questionnaires were completed by parents (predominantly mothers) of 1285 twin pairs aged 5 and 16 years from the volunteer Australian Twin Registry (ATR). Included were a DSM-IV-based ADHD form, the alternative SWAN (Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour scale) and the Developmental Coordination Disorder Questionnaire (DCDQ). Statistical analyses including structural equation modelling were carried out to explore the genetic factors of both disorders. The modelling showed a strong shared additive genetic component between most subtypes of ADHD and DCD to the subtypes of the other disorder. Analyses comparing the two ADHD measures showed an overlap of the symptoms captured by each measure but also significant differences. The DCD-fine motor and ADHD-Inattentive were most strongly linked using the DSM-IV based scale. On the SWAN scale the results were similar but the general coordination scale was also very strongly linked. Implications for the use of different assessment tools are discussed.

The Australian Twin ADHD Project: current status and future directions.

This article describes the Australian Twin Attention-deficit/hyperactivity disorder (ADHD) Project (ATAP), the results of research conducted using this database and plans for future studies. Information has been actively collected from Australian families with twin children since 1991 for the ATAP database. The value of assessing siblings as well as twins is emphasized. Much work has gone into continuing the involvement of families in the study though this does become more difficult when twins reach maturity. The main focus of the project is ADHD in children and adolescents plus comorbid conditions including conduct disorder, oppositional defiant disorder, and generalized anxiety disorder. A major challenge has been how to retain continuity in the assessments, while at the same time covering changes in psychiatric classification, such as the move to Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994). Changes in the scale can affect the reports of twin similarity. Over the years, these twins have become part of other twin studies and future plans include linking different twin databases to investigate the relationships between childhood behavior and adult conditions. Recruitment, assessment and retention of twin families require a major commitment but create a significant resource for collaboration in areas outside the original aim.

Family dysfunction interacts with genes in the causation of antisocial symptoms.

There is emerging evidence of gene-environment interaction effects on conduct problems, both from adoption studies and from a study using a measured genotype. An association between non-violent family dysfunction and conduct problems has also been reported, although not in the context of gene-environment interaction studies. The aim of this study was to examine the interaction of genes and family dysfunction in contributing to conduct problems in young people. Parents of 278 monozygotic and 378 dizygotic twin pairs, aged 5-18, from the CaStANET birth cohort twin register were questioned about zygosity, conduct problems and family environment. Using structural equation modeling we tested for main and interactive effects of genes and family dysfunction modelled as an environmental "moderator variable". Both main and gene-environment interaction effects were highly significant. It was concluded that a risk genotype conferring susceptibility to family dysfunction is responsible for most of the variance in antisocial symptoms in childhood and adolescence.

The development of prosocial behaviour in children and adolescents: a twin study.

BACKGROUND: Childhood psychopathology is associated with both high and low levels of prosocial behaviour. It has been proposed that the development of prosocial behaviour shows emerging and consolidating individual differences as children grow older. The influences on these individual differences have not previously been examined in children and adolescents using multiple raters in a genetically informative design. METHODS: Twin data from 682 families based on parent and teacher reports were used to examine the genetic and environmental influences on prosocial behaviour in 5-16-year-olds. Effects of sex, age and rater were examined. RESULTS: There were no significant differences in the magnitude of genetic and environmental influence on male and female prosocial behaviour. Declining common environment and increasing genetic influences were seen with age. This emerged as a trend in parent data and reached statistical significance in teacher data. When parent and teacher data were examined together in a rater bias model significant bias acting on the parent ratings emerged, in keeping with previous discrepancies between parental and observational measures. There was overlap in the phenotype rated by parents and teachers, with a highly heritable common underlying phenotype. CONCLUSIONS: The influences on the distribution of prosocial behaviour in children and adolescents show declining shared environmental and increasing genetic influences with age. Parental assessments of prosocial behaviour show significantly higher scores than teacher reports and whilst there is overlap in the phenotype rated by parents and teachers, parents show significant bias in their ratings.

Do aggressive and non-aggressive antisocial behaviors in adolescents result from the same genetic and environmental effects?

Antisocial behavior (ASB) in adolescents can broadly be separated into two forms; aggressive and non-aggressive. Both are heritable and it has been suggested that aggressive ASB is more heritable. The extent to which genes contribute to the correlation between the two is unknown. Structural equation modeling was applied to a population-based twin sample of 258 twins pairs aged 11-18 to estimate the heritability of each form of ASB and to estimate the extent to which the phenotypic correlation was the consequence of shared genes and environmental factors. Non-shared environment and genetic factors substantially influenced both forms of ASB. The heritability of aggressive (but not non-aggressive) ASB was significantly higher in girls than in boys. Combining both sexes, a model in which the genetic effects on aggressive and non-aggressive ASB were identical could be rejected. Our results suggest a partial genetic overlap with a specific genetic effect contributing to the variance of aggressive ASB and a stronger genetic effect on aggression in females than in males.

Conduct problems in children and adolescents: a twin study.

BACKGROUND: Evidence supports a genetic influence on conduct problems as a continuous measure of behavior and as a diagnostic category. However, there is a lack of studies using a genetically informative design combined with several different informants and different settings. OBJECTIVES: To examine genetic and environmental influences on conduct problems rated by parent and teacher reports and self-reports and to determine whether their ratings reflect a common underlying phenotype. DESIGN: A twin study design was used to examine conduct problem scores from ratings by teachers, parents, and twins themselves. SETTING: General community. PARTICIPANTS: Twins aged 5 to 17 years participating in the Cardiff Study of All Wales and North England Twins (CaStANET) project. MAIN OUTCOME MEASURES: Conduct problem scale from the Strengths and Difficulties Questionnaire. RESULTS: Conduct problem scores were significantly heritable based on parent and teacher reports and self-reports. Combining data from all 3 informants showed that they are rating a common underlying phenotype of pervasive conduct problems that is entirely genetic, while teacher ratings show separate genetic influences that are not shared with other raters. CONCLUSIONS: Conduct problems are significantly heritable based on parent and teacher reports and self-reports, and are also influenced by environmental effects that impinge uniquely on children from the same family. There is a cross-situational conduct problems' phenotype, underlying the behavior measured by all informants, that is wholly genetic in origin. No significant influence of shared environmental effects was found.