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. Molecular Psychiatry (2006) 11, 934-953.

Summary. Objective. ADHD is frequently accompanied by motor coordination problems. However, the co-occurrence of poor motor performance has received less attention in research than other coexisting problems in ADHD. The underlying mechanisms of this association remain unclear. Therefore, we investigated the prevalence of motor coordination problems in a large sample of children with ADHD, and the relationship between motor coordination problems and inattentive and hyperactive=impulsive symptoms. Furthermore, we assessed whether the association between ADHD and motor coordination problems was comparable across ages and was similar for both genders.Method. We investigated 486 children with ADHD and 269 normal controls. Motor coordination problems were rated by parents (Developmental Coordination Disorder Questionnaire) and teachers (Groningen Motor Observation Scale).Results. Parents and teachers reported motor coordination problems in about one third of children with ADHD. Problems of fine and gross motor skills, coordination skills and motor control were all related to inattentive rather than hyperactive=impulsive symptoms. Relative to controls, motor coordination problems in ADHD were still present in teenagers according to parents; the prevalence diminished somewhat according to teachers. Boys and girls with ADHD were comparably affected, but motor performance in controls was better in girls than in boys.Conclusions. Motor coordination problems were reported in one third of children with ADHD and affected both boys and girls. These problems were also apparent in adolescents with ADHD. Clinicians treating children with ADHD should pay attention to co-occurring motor coordination problems because of the high prevalence and the negative impact of motor coordination problems on daily life.

Executive dysfunction has been postulated as the core deficit in ADHD, although many deficits in lower order cognitive processes have also been identified. By obtaining an appropriate baseline of lower order cognitive functioning light may be shed on as to whether executive deficits result from problems in lower order and/or higher order cognitive processes. We examined motor inhibition and cognitive flexibility in relation to a baseline measure in 816 children from ADHD and control families. Multiple children in a family were tested in order to examine the familiality of the measures. No evidence was found for deficits in motor inhibition or cognitive flexibility in children with ADHD or their nonaffected siblings: Compared to their baseline speed and accuracy of responding, children with ADHD and their (non)affected siblings were not disproportionally slower or inaccurate when demands for motor inhibition or cognitive flexibility were added to the task. However, children with ADHD and their (non)affected siblings were overall less accurate than controls, which could not be attributed to differences in response speed. This suggests that inaccuracy of responding is characteristic of children having (a familial risk for) ADHD. Motor inhibition and cognitive flexibility as operationalized with mean reaction time were found to be familial. It is concluded that poorer performance on executive tasks in children with ADHD and their (non)affected siblings may result from deficiencies in lower order cognitive processes and not (only) from higher order cognitive processes/executive functions.Keywords Inhibition . Set shifting . Endophenotype . Affected and nonaffected siblings . Familiality Attention-Deficit/Hyperactivity Disorder (ADHD) (American Psychiatric Association [APA] 1994) is associated with impairments in the fronto-striatal-basal ganglia neurocircuitry (Casey et al. 1997;Dickstein et al. 2005;Durston et al. 2003;Giedd et al. 2001). These impairments are hypothesized to be (causally) related to deficits in higher order cognitive processes/executive functions (Barkley 1997;Casey et al. 1997;Fuster 2002;Lovejoy et al. 1999;Mehta et al. 2004;Rubia et al. 1999). Executive deficits in working memory, (motor) inhibition, cognitive flexibility and planning are frequently found in children, adolescents and adults with ADHD (Barkley 1997;Boonstra et al. 2005b;Pennington and Ozonoff 1996;Sergeant et al. 2003;Sergeant et al. 2002;Willcutt et al. 2005). As the term 'higher order cognitive processes' suggests, there are also lower order cognitive processes on which higher order cognitive processes build (Halperin and Schulz 2006;Sergeant 2000;Sergeant et al. 2003;Shallice et al. 1996). Lower order cognitive processes, such as encoding, search, decision and response organization are less complex than higher order cognitive processes (Domin 1999;Parisi 1997;Sergeant 2000) and form necessary components for higher order cognitive operations (Baddeley and Della Sala J Abnorm Child Psychol (2007) 35:957-967

Background. Impairments in executive functioning (EF) and intelligence quotient (IQ) are frequently observed in children with attention deficit hyperactivity disorder (ADHD). The aim of this paper was twofold : first, to examine whether both domains are viable endophenotypic candidates for ADHD and second to investigate whether deficits in both domains tend to co-segregate within families.Method. A large family-based design was used, including 238 ADHD families (545 children) and 147 control families (271 children). Inhibition, visuospatial and verbal working memory, and performance and verbal IQ were analysed.Results. Children with ADHD, and their affected and non-affected siblings were all impaired on the EF measures and verbal IQ (though unimpaired on performance IQ) and all measures correlated between siblings. Correlations and sibling cross-correlations were not significant between EF and IQ, though they were significant between the measures of one domain. Group differences on EF were not explained by group differences on IQ and vice versa. The discrepancy score between EF and IQ correlated between siblings, indicating that siblings resembled each other in their EF-IQ discrepancy instead of having generalized impairments across both domains. Siblings of probands who had an EF but not IQ impairment, showed a comparable disproportionate lower EF score in relation to IQ score. The opposite pattern was not significant. Conclusions.The results supported the viability of EF and IQ as endophenotypic candidates for ADHD. Most findings support an independent familial segregation of both domains. Within EF, similar familial factors influenced inhibition and working memory. Within IQ, similar familial factors influenced verbal and performance IQ.

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 (l sib ) 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. INTRODUCTIONAttention deficit hyperactivity disorder (ADHD) is a common and heritable disorder that starts in early childhood and is characterized by developmentally inappropriate levels of hyperactive, impulsive, and inattentive behaviors accompanied by psychosocial impairments. The disorder is known to aggregate in families, with recent estimates suggesting a fourto sixfold increase in the risk for ADHD among first-degree relatives of ADHD probands [Faraone et al., 2000;Brookes et al., 2006a]. Twin studies using parent and teacher rated ADHD symptom scales demonstrate the predominant role of genetic factors with heritability estimates in the range 60-90% [Thapar et al., 1999;Faraone et al., 2005]. Molecular genetic studies using candidate gene association approaches have yielded positive findings with dopamine and related monoamine neurotransmitter genes, in particular with genetic variants of the dopamine transporter, dopamine D4 and D5 receptor genes [reviewed in Asherson and The Image Consortium, 2004;Faraone et al., 2005;Brookes et al., 2006b;Li et al., 2006;Asherson et al., 2007]. Linkage studies using affected sib-pair or extended pedigree approaches have identified chromosomal regions containing putative risk alleles for ADHD [Fisher et al., 2002a;Bakker et al., 2003;Ogdie et al., 2003Ogdie et al., , 2004Ogdie et al., , 2006Arcos-Burgos et al., 2004;Hebebrand et al., 2006].I...