Quantitative linkage for autism spectrum disorders symptoms in attention-deficit/hyperactivity disorder: significant locus on chromosome 7q11.

We studied 261 ADHD probands and 354 of their siblings to assess quantitative trait loci associated with autism spectrum disorder symptoms (as measured by the Children's Social Behavior Questionnaire (CSBQ)) using a genome-wide linkage approach, followed by locus-wide association analysis. A genome-wide significant locus for the CSBQ subscale addressing social interaction was found on chromosome 7q11, with suggestive signals supporting this locus on three other CSBQ subscales. We identified two other suggestive loci for the CSBQ total scale and individual subscales on chromosomes 4q35 and 7p12. Fine-mapping the significantly linked locus resulted in interesting candidate genes, although their association was not significant after permutation testing.

The dopamine receptor D4 7-repeat allele influences neurocognitive functioning, but this effect is moderated by age and ADHD status: an exploratory study.

OBJECTIVES: Evidence suggests the involvement of the dopamine D4 receptor gene (DRD4) in the pathogenesis of ADHD, but the exact mechanism is not well understood. Earlier reports on the effects of DRD4 polymorphisms on neurocognitive and neuroimaging measures are inconsistent. This study investigated the functional consequences of the 7-repeat allele of DRD4 on neurocognitive endophenotypes of ADHD in the Dutch subsample of the International Multicenter ADHD Genetics study. METHODS: Participants were 350 children (5-11.5 years) and adolescents (11.6-19 years) with ADHD and their 195 non-affected siblings. An overall measure of neuropsychological functioning was derived by principal component analysis from five neurocognitive and five motor tasks. The effects of DRD4 and age were examined using Linear Mixed Model analyses. RESULTS: The analyses were stratified for affected and non-affected participants after finding a significant three-way interaction between ADHD status, age and the 7-repeat allele. Apart from a main effect of age, a significant interaction effect of age and DRD4 was found in non-affected but not in affected participants, with non-affected adolescent carriers of the 7-repeat allele showing worse neuropsychological performance. In addition, carrying the 7-repeat allele of DRD4 was related to a significantly worse performance on verbal working memory in non-affected siblings, independent of age. CONCLUSIONS: These results might indicate that the effect of the DRD4 7-repeat allele on neuropsychological functioning is dependent on age and ADHD status.

Perinatal risk factors interacting with catechol O-methyltransferase and the serotonin transporter gene predict ASD symptoms in children with ADHD.

BACKGROUND: Symptoms of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) often co-occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD. METHODS: We studied the association of the catechol O-methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5-HTT) 5-HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre- and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n =439) selected from the TRracking Adolescents' Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children's Social Behavior Questionnaire (CSBQ). RESULTS: No significant main effects of COMT Val158Met, 5-HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p =.008); this interaction reached significance in the TRAILS sample after correction for confounders (p =.02). In the IMAGE sample, the 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p =.02), and also interacted with low birth weight, increasing rigid behavior (p =.03). Findings for 5-HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales. CONCLUSIONS: These findings suggest gene-environment interaction effects on ASD symptoms in children with ADHD.

Identifying loci for the overlap between attention-deficit/hyperactivity disorder and autism spectrum disorder using a genome-wide QTL linkage approach.

OBJECTIVE: The genetic basis for autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD) was addressed using a genome-wide linkage approach. METHOD: Participants of the International Multi-Center ADHD Genetics study comprising 1,143 probands with ADHD and 1,453 siblings were analyzed. The total and subscale scores of the Social Communication Questionnaire (SCQ) were used as quantitative traits for multipoint regression-based linkage analyses on 5,407 autosomal single-nucleotide polymorphisms applying MERLIN-regress software, both without and with inclusion of ADHD symptom scores as covariates. RESULTS: The analyses without ADHD symptom scores as covariates resulted in three suggestive linkage signals, i.e., on chromosomes 15q24, 16p13, and 18p11. Inclusion of ADHD symptom scores as covariates resulted in additional suggestive loci on chromosomes 7q36 and 12q24, whereas the LOD score of the locus on chromosome 15q decreased below the threshold for suggestive linkage. The loci on 7q, 16p, and 18p were found for the SCQ restricted and repetitive subscale, that on 15q was found for the SCQ communication subscale, and that on 12q for the SCQ total score. CONCLUSIONS: Our findings suggest that QTLs identified in this study are ASD specific, although the 15q QTL potentially has pleiotropic effects for ADHD and ASD. This study confirms that genetic factors influence ASD traits along a continuum of severity, as loci potentially underlying ASD symptoms in children with ADHD were identified even though subjects with autism had been excluded from the IMAGE sample, and supports the hypothesis that differential genetic factors underlie the three ASD dimensions.

Externalizing behaviors in preadolescents: familial risk to externalizing behaviors and perceived parenting styles.

The aim was to investigate the contribution of familial risk to externalizing behaviors (FR-EXT), perceived parenting styles, and their interactions to the prediction of externalizing behaviors in preadolescents. Participants were preadolescents aged 10-12 years who participated in TRAILS, a large prospective population-based cohort study in the Netherlands (N = 2,230). Regression analyses were used to determine the relative contribution of FR-EXT and perceived parenting styles to parent and teacher ratings of externalizing behaviors. FR-EXT was based on lifetime parental externalizing psychopathology and the different parenting styles (emotional warmth, rejection, and overprotection) were based on the child's perspective. We also investigated whether different dimensions of perceived parenting styles had different effects on subdomains of externalizing behavior. We found main effects for FR-EXT (vs. no FR-EXT), emotional warmth, rejection, and overprotection that were fairly consistent across rater and outcome measures. More specific, emotional warmth was the most consistent predictor of all outcome measures, and rejection was a stronger predictor of aggression and delinquency than of inattention. Interaction effects were found for FR-EXT and perceived parental rejection and overprotection; other interactions between FR-EXT and parenting styles were not significant. Correlations between FR-EXT and perceived parenting styles were absent or very low and were without clinical significance. Predominantly main effects of FR-EXT and perceived parenting styles independently contribute to externalizing behaviors in preadolescents, suggesting FR-EXT and parenting styles to be two separate areas of causality. The relative lack of gene-environment interactions may be due to the epidemiological nature of the study, the preadolescent age of the subjects, the measurement level of parenting and the measurement level of FR-EXT, which might be a consequence of both genetic and environmental factors.

Effects of maternal and paternal smoking on attentional control in children with and without ADHD.

Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3' untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains.

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.

Undertreatment of Motor Problems in Children with ADHD.

BACKGROUND: Motor problems occur in 30% to 50% of children with ADHD, and have a severe impact on daily life. In clinical practice there seems to be little attention for this comorbidity with the possible consequence that these motor problems go undertreated. METHOD: Clinical interview and questionnaire survey of treatment by physiotherapy and factors predicting treatment of motor problems in 235 children with ADHD and 108 controls. RESULTS: Half of motor-affected children had received physiotherapy. Treated children had more severe motor problems, and less frequently presented with comorbid anxiety and conduct disorder. Treated and untreated children were similar in age, and rated similarly on ADHD inattentive and hyperactive-impulsive scales and parental socio-economic status. CONCLUSION: Currently, undertreatment of motor problems in ADHD occurs. Behavioural factors play a role in referral and intervention.

Externalizing behaviors in preadolescents: familial risk to externalizing behaviors, prenatal and perinatal risks, and their interactions.

BACKGROUND: Accumulating evidence indicates that there is a rich and varied interplay between persons and their environments, which strongly suggests that this involves gene-environment correlations and interactions. We investigated whether familial risk (FR) to externalizing behaviors and prenatal and perinatal risk factors, separately or in interaction with each other, predicted externalizing behaviors. METHODS: The subjects were 10- to 12-year-old preadolescents who were taking part in TRAILS, a large prospective population-based cohort study (N = 2,230). Regression analyses were used to determine the relative contribution of FR and prenatal and perinatal risks to parent and teacher ratings of inattention, hyperactivity/impulsivity aggression, and delinquency. RESULTS: Regression models explained between 6 and 11% of the variance of externalizing behaviors. We found main effects of FR (vs. no FR), macrosomia (birth weight > 4,500 g), maternal prenatal smoking (MPS), pregnancy and delivery complications (PDCs), and gender that were rather consistent across rater and outcome measures. For some outcome measures, the effect of MPS and PDCs depended on the presence of FR. These included both positive and negative interaction effects. Correlations between FR and prenatal and perinatal risks were significant but rather low. CONCLUSIONS: Both main effects and interaction effects of FR and prenatal and perinatal risks contributed to externalizing behaviors in preadolescents, but all effects were of small size. Further research including use of candidate gene polymorphisms is necessary to identify the underlying neurobiological mechanisms of these main and interaction effects.

The dopamine receptor D4 7-repeat allele and prenatal smoking in ADHD-affected children and their unaffected siblings: no gene-environment interaction.

BACKGROUND: The dopamine receptor D4 (DRD4) 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by environment (GxE) interaction of the DRD4 7-repeat allele and smoking during pregnancy on ADHD and oppositional behavior in families from the International Multicenter ADHD Genetics project; and further, to test the hypothesis that the direction of effect of the DRD4 7-repeat allele differs between ADHD affected and unaffected children. METHODS: Linear mixed models were used to assess main and interactive effects of the DRD4 7-repeat allele and smoking during pregnancy in 539 ADHD-affected children and their 407 unaffected siblings, aged 6-17 years. RESULTS: There was some evidence pointing to differential effects of the DRD4 7-repeat allele on ADHD and oppositional symptoms in the affected (fewer symptoms) and unaffected children (increasing ADHD symptoms of teacher ratings). Affected children were more often exposed to prenatal smoking than unaffected children. There were limited main effects of prenatal smoking on severity of symptoms. Given the number of tests performed, no indication was found for GxE interactions. CONCLUSION: Despite the large sample size, no GxE interactions were found. The impact of the DRD4 7-repeat allele might differ, depending on affected status and rater. This finding is discussed in terms of differences in the activity of the dopaminergic system and of different genes involved in rater-specific behaviors.

Differential association between MAOA, ADHD and neuropsychological functioning in boys and girls.

Attention-deficit/hyperactivity disorder (ADHD) is more common in boys than in girls. It has been hypothesized that this sex difference might be related to genes on the X-chromosome, like Monoamine Oxidase A (MAOA). Almost all studies on the role of MAOA in ADHD have focused predominantly on boys, making it unknown whether MAOA also has an effect on ADHD in girls, and few studies have investigated the relationship between MAOA and neuropsychological functioning, yet this may provide insight into the pathways leading from genotype to phenotype. The current study set out to examine the relationship between MAOA, ADHD, and neuropsychological functioning in both boys (265 boys with ADHD and 89 male non-affected siblings) and girls (85 girls with ADHD and 106 female non-affected siblings). A haplotype was used based on three single nucleotide polymorphisms (SNPs) (rs12843268, rs3027400, and rs1137070). Two haplotypes (GGC and ATT) captured 97% of the genetic variance in the investigated MAOA SNPs. The ATT haplotype was more common in non-affected siblings (P = 0.025), conferring a protective effect for ADHD in both boys and girls. The target and direction of the MAOA effect on neuropsychological functioning was different in boys and girls: The ATT haplotype was associated with poorer motor control in boys (P = 0.002), but with better visuo-spatial working memory in girls (P = 0.01). These findings suggest that the genetic and neuropsychological mechanisms underlying ADHD may be different in boys and girls and underline the importance of taking into account sex effects when studying ADHD.

A review and analysis of the relationship between neuropsychological measures and DAT1 in ADHD.

Meta-analyses indicate that the gene coding for the dopamine transporter (DAT1 or SLC6A3) is associated with an increased risk for ADHD. The mechanisms of this gene for ADHD are unclear. We systematically reviewed studies linking the VNTR in the 3' UTR of the DAT1 to neurophysiological and neuropsychological measures. In addition, a broad set of executive/cognitive and motor tests was administered to 350 children (5-11 years) and adolescents (11-19 years) with ADHD and 195 non-affected siblings. Two VNTRs (in intron 8 and the 3' UTR) and four SNPs (two 5' and two 3') in DAT1 were genotyped. The effect of the polymorphisms on neuropsychological functioning was studied. The review indicated that the majority of studies did not find a relation between DAT1 and neurophysiological or neuropsychological measures. In our sample, several of the polymorphisms of DAT1 were associated with ADHD and ADHD was associated with impaired neuropsychological functioning. However, none of the DAT1 polymorphisms was convincingly associated with neuropsychological dysfunctioning. This suggests that the effect of DAT1 on ADHD was not mediated by neuropsychological performance. However, since DAT1 is mainly expressed in the striatum and not the prefrontal cortex, it may influence striatum-related functions (such as delay aversion) more heavily than prefrontal related functions (such as executive functions). Associations of DAT1 with ADHD were only found in adolescents, which may suggest that DAT1 mainly exerts its effect in adolescence, and/or that having a more persistent form of ADHD may mark a more severe or homogeneous genetic form of the disorder.

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.

Neuropsychological endophenotype approach to genome-wide linkage analysis identifies susceptibility loci for ADHD on 2q21.1 and 13q12.11.

ADHD linkage findings have not all been consistently replicated, suggesting that other approaches to linkage analysis in ADHD might be necessary, such as the use of (quantitative) endophenotypes (heritable traits associated with an increased risk for ADHD). Genome-wide linkage analyses were performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. Eight candidate neuropsychological ADHD endophenotypes with heritabilities > 0.2 were used as quantitative traits. In addition, an overall component score of neuropsychological functioning was used. A total of 5407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. Two significant genome-wide linkage signals were found, one for Motor Timing on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span on 13q12.11 (LOD score: 3.959). Ten suggestive linkage signals were found (LOD scores > or = 2) on chromosomes 2p, 2q, 3p, 4q, 8q, 12p, 12q, 14q, and 17q. The suggestive linkage signal for the component score that was found at 2q14.3 (LOD score: 2.878) overlapped with the region significantly linked to Motor Timing. Endophenotype approaches may increase power to detect susceptibility loci in ADHD and possibly in other complex disorders.

Speed, variability, and timing of motor output in ADHD: which measures are useful for endophenotypic research?

Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD.

Motor control in children with ADHD and non-affected siblings: deficits most pronounced using the left hand.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is strongly influenced by heritability. Identifying heritable vulnerability traits (endophenotypes) that mark a relatively high risk of developing the disorder can contribute to the identification of risk genes. A fruitful area for the search for such endophenotypes may be motor control in children with ADHD, since the disorder is frequently accompanied by motor problems. METHOD: The current study used a large sample of 350 children with ADHD, 195 non-affected siblings and 271 normal controls aged 5-19 years. Children were administered two computerised motor control tasks in which they had to trace a path between two circles (Tracking task) and follow a randomly moving target (Pursuit task). Both tasks were performed with both the right and the left hand. RESULTS: Children with ADHD were less precise and stable than controls. Non-affected siblings also deviated from controls, but only on the Tracking task. Group differences were modulated by the use of the right versus the left hand: no group differences emerged when the right hand was used, yet group differences did emerge when the left hand was used. Performance on both tasks was significantly familial. CONCLUSIONS: Imprecision and instability of movements in children with ADHD and in their non-affected siblings as measured by the Tracking task might be suitable endophenotypic candidates: these deficits are familially present in children having ADHD as well as in their non-affected siblings. Motor performance might be best assessed in children using their left hand, because motor control deficits are most pronounced using the left hand. This might relate to right hemispheric brain pathology in children with ADHD (and possibly in their non-affected siblings) that is related to the control of the left hand and/or relate to differential effects of daily life practice on both hands, which may be smaller on the left hand.

Are motor inhibition and cognitive flexibility dead ends in ADHD?

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.