Aisling Mulligan

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 1038 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.

Delay and reward choice in ADHD: an experimental test of the role of delay aversion

Children with attention deficit/hyperactivity disorder (ADHD) choose smaller sooner (SS) over larger later (LL) rewards more than controls. Here we assess the contributions of impulsive drive for immediate rewards (IDIR) and delay aversion (DAv) to this pattern. We also explore the characteristics of, and the degree of familiality in, ADHD SS responders. We had 360 ADHD probands; 349 siblings and 112 controls (aged between 6 to 17 years) chose between SS (1 point after 2 s) and LL reward (2 points after 30 s) outcomes on the Maudsley Index of Delay Aversion (Kuntsi, Oosterlaan, & Stevenson, 2001): Under one condition SS choice led to less overall trial delay under another it did not. ADHD participants chose SS more than controls under both conditions. This effect was larger when SS choice reduced trial delay. ADHD SS responders were younger, had lower IQ, more conduct disorder and had siblings who were more likely to be SS responders themselves. The results support a dual component model in which both IDIR and DAv contribute to SS choice in ADHD. SS choice may be a marker of an ADHD motivational subtype.

Autism symptoms in Attention-Deficit/Hyperactivity Disorder: A Familial trait which Correlates with Conduct, Oppositional Defiant, Language and Motor Disorders

It is hypothesised that autism symptoms are present in Attention-Deficit/Hyperactivity Disorder (ADHD), are familial and index subtypes of ADHD. Autism symptoms were compared in 821 ADHD probands, 1050 siblings and 149 controls. Shared familiality of autism symptoms and ADHD was calculated using DeFries-Fulker analysis. Autism symptoms were higher in probands than siblings or controls, and higher in male siblings than male controls. Autism symptoms were familial, partly shared with familiality of ADHD in males. Latent class analysis using SCQ-score yielded five classes; Class 1(31%) had few autism symptoms and low comorbidity; Classes 2–4 were intermediate; Class 5(7%) had high autism symptoms and comorbidity. Thus autism symptoms in ADHD represent a familial trait associated with increased neurodevelopmental and oppositional/conduct disorders.

DSM-IV Combined Type ADHD Shows Familial Association With Sibling Trait Scores: A Sampling Strategy For QTL Linkage

Attention deficit hyperactivity disorder (ADHD) is a discrete clinical syndrome characterized by the triad of inattention, hyperactivity, and impulsivity in the context of marked impairments. Molecular genetic studies have been successful in identifying genetic variants associated with ADHD, particularly with DSM‐IV inattentive and combined subtypes. Quantitative trait locus (QTL) approaches to linkage and association mapping have yet to be widely used in ADHD research, although twin studies investigating individual differences suggest that genetic liability for ADHD is continuously distributed throughout the population, underscoring the applicability of quantitative dimensional approaches. To investigate the appropriateness of QTL approaches, we tested the familial association between 894 probands with a research diagnosis of DSM‐IV ADHD combined type and continuous trait measures among 1,135 of their siblings unselected for phenotype. The sibling recurrence rate for ADHD combined subtype was 12.7%, yielding a sibling recurrence risk ratio (λsib) of 9.0. Estimated sibling correlations around 0.2–0.3 are similar to those estimated from the analysis of fraternal twins in population twin samples. We further show that there are no threshold effects on the sibling risk for ADHD among the ADHD probands; and that both affected and unaffected siblings contributed to the association with ADHD trait scores. In conclusion, these data confirm the main requirement for QTL mapping of ADHD by demonstrating that narrowly defined DSM‐IV combined type probands show familial association with dimensional ADHD symptom scores amongst their siblings.

Performance variability, impulsivity errors and the impact of incentives as gender-independent endophenotypes for ADHD.

BACKGROUND Attention-deficit hyperactivity disorder (ADHD) is one of the most common and highly heritable child psychiatric disorders. There is strong evidence that children with ADHD show slower and more variable responses in tasks such as Go/Nogo tapping aspects of executive functions like sustained attention and response control which may be modulated by motivational factors and/or state-regulation processes. The aim of this study was (1) to determine if these executive functions may constitute an endophenotype for ADHD; (2) to investigate for the first time whether known modulators of these executive functions may also be familial; and (3) to explore whether gender has an impact on these measures. METHODS Two hundred and five children with ADHD combined type, 173 nonaffected biological siblings and 53 controls with no known family history of ADHD were examined using a Go/Nogo task in the framework of a multi-centre study. Performance-measures and modulating effects of event-rate and incentives were examined. Shared familial effects on these measures were assessed, and the influence of gender was tested. RESULTS Children with ADHD responded more slowly and variably than nonaffected siblings or controls. Nonaffected siblings showed intermediate scores for reaction-time variability, false alarms and omission errors under fast and slow event-rates. A slower event-rate did not lead to reduced performance specific to ADHD. In the incentive condition, mean reaction-times speeded up and became less variable only in children with ADHD and their nonaffected siblings, while accuracy was improved in all groups. Males responded faster, but also committed more false alarms. There were no interactions of group by gender. CONCLUSIONS Reaction-time variability and accuracy parameters could be useful neuropsychological endophenotypes for ADHD. Performance-modulating effects of incentives suggested a familially driven motivational dysfunction which may play an important role on etiologic pathways and treatment approaches for ADHD. The effects of gender were independent of familial effects or ADHD-status, which in turn suggests that the proposed endophenotypes are independent of gender.

Autism symptoms in Attention-Deficit/Hyperactivity Disorder: a familial trait which correlates with conduct, oppositional defiant, language and motor disorders.

It is hypothesised that autism symptoms are present in Attention-Deficit/Hyperactivity Disorder (ADHD), are familial and index subtypes of ADHD. Autism symptoms were compared in 821 ADHD probands, 1050 siblings and 149 controls. Shared familiality of autism symptoms and ADHD was calculated using DeFries-Fulker analysis. Autism symptoms were higher in probands than siblings or controls, and higher in male siblings than male controls. Autism symptoms were familial, partly shared with familiality of ADHD in males. Latent class analysis using SCQ-score yielded five classes; Class 1(31%) had few autism symptoms and low comorbidity; Classes 2–4 were intermediate; Class 5(7%) had high autism symptoms and comorbidity. Thus autism symptoms in ADHD represent a familial trait associated with increased neurodevelopmental and oppositional/conduct disorders.

Conduct Disorder and ADHD: Evaluation of Conduct Problems as a Categorical and Quantitative Trait in the International Multicentre ADHD Genetics Study

Attention‐deficit/hyperactivity disorder (ADHD) is typically characterized by inattention, excessive motor activity, impulsivity, and distractibility. Individuals with ADHD have significant impairment in family and peer relations, academic functioning, and show high co‐morbidity with a wide range of psychiatric disorders including oppositional defiant disorder (ODD), conduct disorder (CD), anxiety disorder, depression, substance abuse, and pervasive developmental disorder (PDD). Family studies suggest that ADHD + CD represents a specific subtype of the ADHD disorder with familial risk factors only partly overlapping with those of ADHD alone. We performed a hypothesis‐free analysis of the GAIN–ADHD sample to identify markers and genes important in the development of conduct problems in a European cohort of individuals with ADHD. Using the Family‐Based Association Test (FBAT) package we examined three measures of conduct problems in 1,043,963 autosomal markers. This study is part of a series of exploratory analyses to identify candidate genes that may be important in ADHD and ADHD‐related traits, such as conduct problems. We did not find genome‐wide statistical significance (P < 5 × 10−7) for any of the tested markers and the three conduct problem traits. Fifty‐four markers reached strong GWA signals (P < 10−5). We discuss these findings in the context of putative candidate genes and the implications of these findings in the understanding of the etiology of ADHD + CD. We aimed to achieve insight into the genetic etiology of a trait using a hypothesis‐free study design and were able to identify a number of biologically interesting markers and genes for follow‐up studies.

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband–sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, ∼95 cM) and Dutch (LOD>1, ∼100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.

Co-transmission of conduct problems with attention-deficit= hyperactivity disorder: familial evidence for a distinct disorder

SummaryCommon disorders of childhood and adolescence are attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). For one to two cases in three diagnosed with ADHD the disorders may be comorbid. However, whether comorbid conduct problems (CP) represents a separate disorder or a severe form of ADHD remains controversial. We investigated familial recurrence patterns of the pure or comorbid condition in families with at least two children and one definite case of DSM-IV ADHDct (combined-type) as part of the International Multicentre ADHD Genetics Study (IMAGE). Using case diagnoses (PACS, parental account) and symptom ratings (Parent/Teacher Strengths and Difficulties [SDQ], and Conners Questionnaires [CPTRS]) we studied 1009 cases (241 with ADHDonly and 768 with ADHD + CP), and their 1591 siblings. CP was defined as ≥4 on the SDQ conduct-subscale, and T ≥ 65, on Conners’ oppositional-score. Multinomial logistic regression was used to ascertain recurrence risks of the pure and comorbid conditions in the siblings as predicted by the status of the cases. There was a higher relative risk to develop ADHD + CP for siblings of cases with ADHD + CP (RRR = 4.9; 95%CI: 2.59–9.41); p < 0.001) than with ADHDonly. Rates of ADHDonly in siblings of cases with ADHD + CP were lower but significant (RRR = 2.9; 95%CI: 1.6–5.3, p < 0.001). Children with ADHD + CP scored higher on the Conners ADHDct symptom-scales than those with ADHDonly. Our finding that ADHD + CP can represent a familial distinct subtype possibly with a distinct genetic etiology is consistent with a high risk for cosegregation. Further, ADHD + CP can be a more severe disorder than ADHDonly with symptoms stable from childhood through adolescence. The findings provide partial support for the ICD-10 distinction between hyperkinetic disorder (F90.0) and hyperkinetic conduct disorder (F90.1).

Attention Network Hypoconnectivity With Default and Affective Network Hyperconnectivity in Adults Diagnosed With Attention-Deficit/Hyperactivity Disorder in Childhood

IMPORTANCE The neurobiological underpinnings of attention-deficit/hyperactivity disorder (ADHD) and particularly those associated with the persistence of ADHD into adulthood are not yet well understood. The correlation patterns in spontaneous neural fluctuations at rest are known as resting-state functional connectivity (RSFC) and could characterize ADHD-specific connectivity changes. OBJECTIVE To determine the specific location of possible ADHD-related differences in RSFC between adults diagnosed as having ADHD in childhood and control subjects. DESIGN Using resting-state functional magnetic resonance imaging, we calculated and compared functional connectivity from attention, affective, default, and cognitive control networks involved in the psychopathology of ADHD between the ADHD and control groups. SETTING University psychiatric service and magnetic resonance imaging research center. PARTICIPANTS Sixteen drug-free adults (5 women and 11 men; mean age, 24.5 years) diagnosed with combined-type ADHD in childhood and 16 healthy controls matched for age (mean age, 24.4 years), sex, handedness, and educational level recruited from the community. INTERVENTION Functional magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Connectivity data from ventral and dorsal attention, affective, default, and cognitive control networks and ADHD symptoms derived from ADHD-specific rating instruments. RESULTS Adults with ADHD showed significantly decreased RSFC within the attention networks and increased RSFC within the affective and default mode and the right lateralized cognitive control networks compared with healthy controls (P < .01, familywise error for whole-brain cluster correction). Lower RSFC in the ventral and dorsal attention network was significantly correlated with higher levels of ADHD symptoms (P < .001). CONCLUSIONS AND RELEVANCE These RSFC findings might underpin a biological basis for adult ADHD and are functionally related to persistent inattention, disturbance in cognitive control, and emotional dysregulation in adults with ADHD. These findings need to be understood in the context of all aspects of brain function in ADHD.