Genetic architecture of ADHD and overlap with other psychiatric disorders and cognition-related phenotypes.

Attention-deficit/hyperactivity disorder (ADHD) co-occurs with many other psychiatric disorders and traits. In this review, we summarize and interpret the existing literature on the genetic architecture of these comorbidities based on hypothesis-generating approaches. Quantitative genetic studies indicate that genetic factors play a substantial role in the observed co-occurrence of ADHD with many different disorders and traits. Molecular genetic correlations derived from genome-wide association studies and results of studies based on polygenic risk scores confirm the general pattern but provide effect estimates that are smaller than those from twin studies. The identification of the specific genetic variants and biological pathways underlying co-occurrence using genome-wide approaches is still in its infancy. The first analyses of causal inference using genetic data support causal relationships between ADHD and comorbid disorders, although bidirectional effects identified in some instances point to complex relationships. While several issues in the methodology and inferences from the results are still to be overcome, this review shows that the co-occurrence of ADHD with many psychiatric disorders and traits is genetically interpretable.

Association of preterm birth with ADHD-like cognitive impairments and additional subtle impairments in attention and arousal malleability.

BACKGROUND: Whilst preterm-born individuals have an increased risk of developing attention-deficit/hyperactivity disorder (ADHD), and are reported to have ADHD-like attention and arousal impairments, direct group comparisons are scarce. METHODS: We directly compared preterm-born adolescents (n = 186) to term-born adolescents with ADHD (n = 69), and term-born controls (n = 135), aged 11-23, on cognitive-performance, event-related potential and skin conductance level (SCL) measures associated with attention and arousal. The measures are from baseline and fast-incentive conditions of a four-choice reaction time task, previously shown to discriminate between the individuals with ADHD and controls. We aimed to establish whether preterm-born adolescents show: (a) identical cognitive-neurophysiological impairments to term-born adolescents with ADHD (b) possible additional impairments, and whether (c) the observed impairments correlate with ADHD symptom scores. RESULTS: The preterm group, like the term-born ADHD group, showed increased mean reaction time (MRT) and reaction time variability (RTV) in the baseline condition, and attenuated contingent negative variation (CNV) amplitude (response preparation) in the fast-incentive condition. The preterm group, only, did not show significant within-group adjustments in P3 amplitude (attention allocation) and SCL (peripheral arousal). Dimensional analyses showed that ADHD symptoms scores correlated significantly with MRT, RTV and CNV amplitude only. CONCLUSIONS: We find impairments in cognition and brain function in preterm-born adolescents that are linked to increased ADHD symptoms, as well as further impairments, in lack of malleability in neurophysiological processes. Our findings indicate that such impairments extend at least to adolescence. Future studies should extend these investigations into adulthood.

Six-year follow-up study of combined type ADHD from childhood to young adulthood: Predictors of functional impairment and comorbid symptoms.

BACKGROUND: ADHD in childhood is associated with development of negative psychosocial and behavioural outcomes in adults. Yet, relatively little is known about which childhood and adulthood factors are predictive of these outcomes and could be targets for effective interventions. To date follow-up studies have largely used clinical samples from the United States with children ascertained at baseline using broad criteria for ADHD including all clinical subtypes or the use of DSM III criteria. AIMS: To identify child and adult predictors of comorbid and psychosocial comorbid outcomes in ADHD in a UK sample of children with DSM-IV combined type ADHD. METHOD: One hundred and eighteen adolescents and young adults diagnosed with DSM-IV combined type ADHD in childhood were followed for an average of 6years. Comorbid mental health problems, drug and alcohol use and police contact were compared for those with persistent ADHD, sub-threshold ADHD and population norms taken from the Adult Psychiatric Morbidity Study 2007. Predictors included ADHD symptomology and gender. RESULTS: Persistent ADHD was associated with greater levels of anger, fatigue, sleep problems and anxiety compared to sub-threshold ADHD. Comorbid mental health problems were predicted by current symptoms of hyperactivity-impulsivity, but not by childhood ADHD severity. Both persistent and sub-threshold ADHD was associated with higher levels of drug use and police contact compared to population norms. CONCLUSIONS: Young adults with a childhood diagnosis of ADHD showed increased rates of comorbid mental health problems, which were predicted by current levels of ADHD symptoms. This suggests the importance of the continuing treatment of ADHD throughout the transitional years and into adulthood. Drug use and police contact were more common in ADHD but were not predicted by ADHD severity in this sample.

Disorder-specific and shared neurophysiological impairments of attention and inhibition in women with attention-deficit/hyperactivity disorder and women with bipolar disorder.

BACKGROUND: In adults, attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) have certain overlapping symptoms, which can lead to uncertainty regarding the boundaries of the two disorders. Despite evidence of cognitive impairments in both disorders separately, such as in attentional and inhibitory processes, data on direct comparisons across ADHD and BD on cognitive-neurophysiological measures are as yet limited. METHOD: We directly compared cognitive performance and event-related potential measures from a cued continuous performance test in 20 women with ADHD, 20 women with BD (currently euthymic) and 20 control women. RESULTS: The NoGo-N2 was attenuated in women with BD, reflecting reduced conflict monitoring, compared with women with ADHD and controls (both p < 0.05). Both ADHD and BD groups showed a reduced NoGo-P3, reflecting inhibitory control, compared with controls (both p < 0.05). In addition, the contingent negative variation was significantly reduced in the ADHD group (p = 0.05), with a trend in the BD group (p = 0.07), compared with controls. CONCLUSIONS: These findings indicate potential disorder-specific (conflict monitoring) and overlapping (inhibitory control, and potentially response preparation) neurophysiological impairments in women with ADHD and women with BD. The identified neurophysiological parameters further our understanding of neurophysiological impairments in women with ADHD and BD, and are candidate biomarkers that may aid in the identification of the diagnostic boundaries of the two disorders.

Everyday emotional experience of adults with attention deficit hyperactivity disorder: evidence for reactive and endogenous emotional lability.

BACKGROUND: Emotional lability (EL), characterized by negative emotional traits and emotional instability, is frequently reported in children and adults with attention deficit hyperactivity disorder (ADHD). However, EL is primarily assessed using retrospective self-report, which is subject to reporting bias and does not consider the potential influence of positive and negative everyday experiences. METHOD: Ambulatory assessment was carried out in 41 men with ADHD without co-morbidity, current medication or substance abuse, and 47 healthy control participants. Reports of negative and positive emotions (irritability, frustration, anger, happiness, excitement) and the occurrence of bad and good events were completed eight times daily during a working week. Group differences in emotional intensity and instability were investigated using multilevel models, and explored in relation to bad and good events and the Affective Lability Scale - Short Form (ALS-SF), an EL questionnaire. RESULTS: The ADHD group reported significantly more frequent bad events, heightened intensity and instability of irritability and frustration, and greater intensity of anger. The results for positive emotions were equivocal or negative. Bad events significantly contributed to the intensity and instability of negative emotions, and showed a stronger influence in the ADHD group. However, covariation for their effect did not eliminate group differences. Small-to-moderate correlations were seen between intensity and instability of negative emotions and the ALS-SF. CONCLUSIONS: Adults with ADHD report heightened intensity and instability of negative emotions in daily life. The results suggest two components of EL in ADHD: a reactive component responsive to bad events and an endogenous component, independent of negative everyday events.

Different heritabilities but shared etiological influences for parent, teacher and self-ratings of ADHD symptoms: an adolescent twin study.

BACKGROUND: Parent and teacher ratings of attention deficit hyperactivity disorder (ADHD) symptoms yield high estimates of heritability whereas self-ratings typically yield lower estimates. To understand why, the present study examined the etiological overlap between parent, teacher and self-ratings of ADHD symptoms in a population-based sample of 11-12-year-old twins. Method Participants were from the Twins Early Development Study (TEDS). ADHD symptoms were assessed using the Strengths and Difficulties Questionnaire (SDQ) hyperactivity scale completed by parents, teachers and children. Structural equation modeling was used to examine genetic and environmental contributions to phenotypic variance/covariance. RESULTS: The broad-sense heritability of ADHD symptoms was 82% for parent ratings, 60% for teacher ratings and 48% for self-ratings. Post-hoc analyses revealed significantly higher heritability for same-teacher than different-teacher ratings of ADHD (76% v. 49%). A common pathway model best explained the relationship between different informant ratings, with common genetic influences accounting for 84% of the covariance between parent, teacher and self-rated ADHD symptoms. The remaining variance was explained by rater-specific genetic and non-shared environmental influences. CONCLUSIONS: Despite different heritabilities, there were shared genetic influences for parent, teacher and self-ratings of ADHD symptoms, indicating that different informants rated some of the same aspects of behavior. The low heritability estimated for self-ratings and different-teacher ratings may reflect increased measurement error when different informants rate each twin from a pair, and/or greater non-shared environmental influences. Future studies into the genetic influences on ADHD should incorporate informant data in addition to self-ratings to capture a pervasive, heritable component of ADHD symptomatology.

Genetic analysis of reaction time variability: room for improvement?

BACKGROUND: Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures 'state regulation'. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores. Method We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265). RESULTS: Phenotypic and genetic/familial correlations were consistently high (0.72-0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r = 0.75-0.83). CONCLUSIONS: Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyses.

Bigger families fare better: a novel method to estimate rater contrast effects in parental ratings on ADHD symptoms.

Many twin studies on parental ratings of attention deficit hyperactivity disorder (ADHD) symptoms report low or negative DZ correlations. The observed differences in MZ and DZ variances indicate sibling contrast effects, which appear to reflect a bias in parent ratings. Knowledge of the factors that contribute to this rater contrast effect is, however, limited. Using parent-rated ADHD symptoms from the Twins' Early Development Study and a novel application of a twin model, we explored a range of socio-demographic variables (ethnicity, socio-economic status, and family size), as potential contributors to contrast effects and their interactive effect with gender composition of twin pairs. Gender did moderate contrast effects but only in DZ opposite-sex twin pairs. Family size also showed a moderating effect on rater contrast effects, which was further modified by gender. We further observed an effect of rating scale, with the DSM-IV ADHD subscale of the Revised Conners' Parent Rating Scale more resistant to contrast effects than shorter scales of ADHD symptoms. The improved identification of situations where the accuracy of the most common informant of childhood ADHD symptoms-parents-is compromised as a result of rater bias, might have implications for future research on ADHD.

Parents and teachers make different contributions to a shared perspective on hyperactive-impulsive and inattentive symptoms: a multivariate analysis of parent and teacher ratings on the symptom domains of ADHD.

Attention deficit hyperactivity disorder (ADHD) is characterised by developmentally inappropriate and impairing levels of inattentive and hyperactive-impulsive behaviours. We aimed to investigate the differential effects of parent and teacher ratings on inattention and hyperactivity-impulsivity and the extent of genetic overlap between the two behavioural dimensions. Multivariate structural equation modelling was performed on DSM-IV based ADHD ratings by parents and teachers collected on a general population sample of 672 twin pairs, at ages 7-10 years. This study is the first to simultaneously use parent and teacher ratings in twin modelling to examine the effects of different raters on the two behavioural dimensions of ADHD. The findings indicated that hyperactivity-impulsivity and inattention load on to separate latent factors that represent a common behavioural view for both parents and teachers, although there are additional aspects to the observations of these behaviours that are unique to each type of rater. The findings further indicate some shared aetiology for hyperactivity-impulsivity and inattention as measured by both parent and teacher ratings, in agreement with previous findings on the aetiology of the two symptom dimensions of ADHD.

The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ.

BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD: Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

Separation of genetic influences on attention deficit hyperactivity disorder symptoms and reaction time performance from those on IQ.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) shows a strong phenotypic and genetic association with reaction time (RT) variability, considered to reflect lapses in attention. Yet we know little about whether this aetiological pathway is shared with other affected cognitive processes in ADHD, such as lower IQs or the generally slower responses (mean RTs). We aimed to address the question of whether a shared set of genes exist that influence RT variability, mean RT, IQ and ADHD symptom scores, or whether there is evidence of separate aetiological pathways. METHOD: Multivariate structural equation modelling on cognitive tasks data (providing RT data), IQ and ADHD ratings by parents and teachers collected on general population sample of 1314 twins, at ages 7-10 years. RESULTS: Multivariate structural equation models indicated that the shared genetic influences underlying both ADHD symptom scores and RT variability are also shared with those underlying mean RT, with both types of RT data largely indexing the same underlying liability. By contrast, the shared genetic influences on ADHD symptom scores and RT variability (or mean RT) are largely independent of the genetic influences that ADHD symptom scores share with IQ. CONCLUSIONS: The finding of unique aetiological pathways between IQ and RT data, but shared components between mean RT, RT variability and ADHD symptom scores, illustrates key influences in the genetic architecture of the cognitive and energetic processes that underlie the behavioural symptoms of ADHD. In addition, the multivariate genetic model fitting findings provide valuable information for future molecular genetic analyses.

Replication of a rare protective allele in the noradrenaline transporter gene and ADHD.

Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1,038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

Co-occurrence of ADHD and low IQ has genetic origins.

Previous studies show that the symptoms of attention deficit hyperactivity disorder (ADHD) and lower intelligence quotient (IQ) covary in children. We investigated the aetiology of this association in a large population-based sample of 5-year-old twins. The twins were individually assessed on an IQ test, and data on ADHD symptoms were obtained from mother interviews and teacher ratings. Confirming previous studies, the phenotypic correlation between ADHD symptom scores and IQ was -0.3 and, in a categorical analysis, children with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) ADHD research diagnosis obtained IQ scores nine points lower, on average, than comparison children. We show here that the co-occurrence of ADHD and lower IQ has genetic origins: 86% of the association between ADHD symptom scores and IQ, and 100% of the association between ADHD diagnosis and IQ, was accounted for by genetic influences that are shared by ADHD and IQ. Some candidate genes for ADHD could also contribute to variation in IQ or vice versa.

Psychological mechanisms in hyperactivity: I. Response inhibition deficit, working memory impairment, delay aversion, or something else?

This study tested the predictions of three different theories of hyperactivity: response inhibition deficit, working memory impairment, and delay aversion. A sample of 51 pervasively hyperactive children and 119 control children, identified by screening a general population sample of 1,316 twin pairs, were assessed on tests relating to each of these theories. The hyperactive group performed worse than the control group on the delay aversion measure and some of the working memory tasks. Controlling for IQ removed the significant group differences on the working memory measures, however. There were no significant group differences on the inhibition variables derived from the stop task. However, there was evidence of a pattern of responding on the stop task that was strongly characteristic of hyperactivity: hyperactive children were variable in their speed, generally slow and inaccurate in responding. This pattern of responses may indicate a nonoptimal effort/ activation state. Hyperactive girls were indistinguishable from hyperactive boys in their performance on the tasks.

Psychological mechanisms in hyperactivity: II. The role of genetic factors.

The main aim of this study was to combine two research approaches to hyperactivity: the behaviour genetic approach and the testing of psychological theories of hyperactivity. For a sample of 268 twin pairs aged 7-11 years we obtained ratings on the Conners' scales from both teachers (CTRS-28) and parents (CPRS-48). Forty-six hyperactive twin pairs (pairs in which at least one twin was pervasively hyperactive) and 47 control twin pairs were assessed on a psychological test battery. Confirming findings from previous twin studies, a substantial proportion of the variance in hyperactivity considered as a dimension was due to genetic effects. There was significant evidence of genetic effects also on extreme hyperactivity, although the present group heritability estimates were somewhat lower than those reported in most previous studies. We investigated the possibility that the psychological mechanisms we reported to be associated with hyperactivity (Kuntsi, Oosterlaan, & Stevenson, 2001) share common genetic factors with hyperactive behaviour. The data produced significant evidence of such shared genetic effects only on hyperactivity and the variability of reaction times. Given that the high variability in speed of responding would indicate a state-regulation problem, this is the psychological mechanism that could possibly be the "link" between genetic effects and hyperactive behaviour.

Hyperactivity in children: a focus on genetic research and psychological theories.

Hyperactivity has attracted a large amount of research interest in recent years. Here we review developments in genetic research and in research testing psychological theories of the condition. Family, adoptee and twin studies indicate a strong role for genetic factors in the etiology of hyperactivity. Evidence is emerging also from molecular genetic studies, implicating specific genes that may be involved. At the level of cognitive functioning, a divided, focused or sustained attention deficit does not seem to be a 'core' deficit in hyperactivity. Although children with hyperactivity often perform poorly on certain executive function tasks, there is disagreement about the interpretation of these findings. The association reported in some studies between a slow inhibitory process and hyperactivity may reflect a generally slow, variable in speed and inaccurate pattern of responding. Hypotheses about psychological mechanisms such as state regulation or delay aversion provide alternative, and particularly encouraging, interpretations of the findings. We discuss the possible integration of the two lines of research--those of genetic research and research on psychological mechanisms.

Parents' and teachers' ratings of problem behaviours in children: genetic and contrast effects.

We obtained ratings on the Conners' scales from teachers (CTRS-28) and parents (CPRS-48) for 61 monozygotic and 64 dizygotic twin pairs, aged between 7 and 11 years. Model-fitting analyses were carried out to estimate the extent of genetic and environmental influences on problem behaviours, and to explore possible contrast effects in ratings by parents and teachers. Confirming previous findings with other measures, there was evidence of moderate to strong genetic effects on a range of problem behaviours. Parents' ratings on the Anxiety, Impulsive-Hyperactive and Learning Problem sub-scales showed significant evidence of contrast effects. There was no evidence of such rater bias or competitive sibling interaction effects in ratings by teachers, or in parents' ratings on the Conduct Problem and Psychosomatic sub-scales.

Ring-X chromosomes: their cognitive and behavioural phenotype.

We tested the cognitive abilities and educational attainments of 47 patients with a ring X chromosome, to evaluate the extent to which these variables correlated with failure of r(X) inactivation and with mosaicism. We found possession of a r(X) chromosome was associated with an increased risk of significant learning difficulties, and with associated behavioural maladjustment, compared with 45,X Turner females. Nearly a third had been educated outside mainstream schools. The proportion of cells in peripheral blood containing an inactivated r(X) chromosome was negatively correlated with nonverbal IQ. The parental origin of the normal chromosome did not appear to affect adjustment or abilities. In a minority of r(X) cases associated with mental retardation, there had been a failure to inactivate the ring, due to loss of the XIST locus. However, failure of X-inactivation was not necessarily associated with a severe phenotype. The degree of impairment in IQ depended on the size of the active ring, and hence was proportionate to the number of (as yet unidentified) genes whose functional disomy affected brain development and functioning.