Attention-deficit/hyperactivity Disorder Genetics Study Research Articles

Neurocognitive markers of late‐onset ADHD: a 6‐year longitudinal study

There is an increased interest in 'late-onset' attention-deficit/hyperactivity disorder (ADHD), referring to the onset of clinically significant ADHD symptoms after the age of 12years. This study aimed to examine whether unaffected siblings with late-onset ADHD could be differentiated from stable unaffected siblings by their neurocognitive functioning in childhood. We report findings from a 6-year prospective, longitudinal study of the Dutch part of the International Multicenter ADHD Genetics (IMAGE) study, including individuals with childhood-onset (persistent) ADHD (n=193), their siblings with late-onset ADHD (n=34), their stable unaffected siblings (n=111) and healthy controls (n=186). At study entry (mean age: 11.3) and follow-up (mean age: 17.01), participants were assessed for ADHD by structured psychiatric interviews and multi-informant questionnaires. Several neurocognitive functions were assessed at baseline and after 6years, including time reproduction, timing variability (reaction time variability and time production variability), reaction time speed, motor control and working memory; intelligence was taken as a measure of overall neurocognitive functioning. Siblings with late-onset ADHD were similar to individuals with childhood-onset ADHD in showing longer reaction times and/or higher error rates on all neurocognitive measures at baseline and follow-up, when compared to healthy controls. They differed from stable unaffected siblings (who were similar to healthy controls) by greater reaction time variability and timing production variability at baseline. No significant group by time interaction was found for any of the tasks. For unaffected siblings of individuals with ADHD, reaction time variability and timing production variability may serve as neurocognitive marker for late-onset ADHD.

Shared alterations in resting-state brain connectivity in adults with attention-deficit/hyperactivity disorder and their unaffected first-degree relatives.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental condition that often persists into adulthood with extensive negative consequences on quality of life. Despite emerging evidence indicating the genetic basis of ADHD, investigations into the familial expression of latent neurocognitive traits remain limited. In a group of adult ADHD probands (n = 20), their unaffected first-degree relatives (n = 20) and typically developing control participants (n = 20), we assessed endophenotypic alterations in the default mode network (DMN) connectivity during resting-state functional magnetic resonance imaging in relation to cognitive performance and clinical symptoms. In an external validation step, we also examined the dimensional nature of this neurocognitive trait in a sample of unrelated healthy young adults (n = 100) from the Human Connectome Project (HCP). The results illustrated reduced anti-correlations between the posterior cingulate cortex/precuneus and right middle frontal gyrus that was shared between adult ADHD probands and their first-degree relatives, but not with healthy controls. The observed connectivity alterations were linked to higher ADHD symptoms that was mediated by performance in a sustained attention task. Moreover, this brain-based neurocognitive trait dimensionally explained ADHD symptom variability in the HCP sample. Alterations in the default mode connectivity may represent a dimensional endophenotype of ADHD, hence a significant aspect of the neuropathophysiology of this disorder. As such, brain network organisation can potentially be employed as an important neurocognitive trait to enhance statistical power of genetic studies in ADHD and as a surrogate efficacy endpoint in the development of novel pharmaceuticals.

Familiality of Co-existing ADHD and Tic Disorders: Evidence from a Large Sibling Study.

Background: The association of attention-deficit/hyperactivity disorder (ADHD) and tic disorder (TD) is frequent and clinically important. Very few and inconclusive attempts have been made to clarify if and how the combination of ADHD+TD runs in families.Aim: To determine the first time in a large-scale ADHD sample whether ADHD+TD increases the risk of ADHD+TD in siblings and, also the first time, if this is independent of their psychopathological vulnerability in general.Methods: The study is based on the International Multicenter ADHD Genetics (IMAGE) study. The present sub-sample of 2815 individuals included ADHD-index patients with co-existing TD (ADHD+TD, n = 262) and without TD (ADHD–TD, n = 947) as well as their 1606 full siblings (n = 358 of the ADHD+TD index patients and n = 1248 of the ADHD-TD index patients). We assessed psychopathological symptoms in index patients and siblings by using the Strength and Difficulties Questionnaire (SDQ) and the parent and teacher Conners' long version Rating Scales (CRS). For disorder classification the Parental Account of Childhood Symptoms (PACS-Interview) was applied in n = 271 children. Odds ratio with the GENMOD procedure (PROCGENMOD) was used to test if the risk for ADHD, TD, and ADHD+TD in siblings was associated with the related index patients' diagnoses. In order to get an estimate for specificity we compared the four groups for general psychopathological symptoms.Results: Co-existing ADHD+TD in index patients increased the risk of both comorbid ADHD+TD and TD in the siblings of these index patients. These effects did not extend to general psychopathology.Interpretation: Co-existence of ADHD+TD may segregate in families. The same holds true for TD (without ADHD). Hence, the segregation of TD (included in both groups) seems to be the determining factor, independent of further behavioral problems. This close relationship between ADHD and TD supports the clinical approach to carefully assess ADHD in any case of TD.

Enlarged striatal volume in adults with ADHD carrying the 9-6 haplotype of the dopamine transporter gene DAT1.

The dopamine transporter gene, DAT1 (SLC6A3), has been studied extensively as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). Different alleles of variable number of tandem repeats (VNTRs) in this gene have been associated with childhood ADHD (10/10 genotype and haplotype 10-6) and adult ADHD (haplotype 9-6). This suggests a differential association depending on age, and a role of DAT1 in modulating the ADHD phenotype over the lifespan. The DAT1 gene may mediate susceptibility to ADHD through effects on striatal volumes, where it is most highly expressed. In an attempt to clarify its mode of action, we examined the effect of three DAT1 alleles (10/10 genotype, and the haplotypes 10-6 and 9-6) on bilateral striatal volumes (nucleus accumbens, caudate nucleus, and putamen) derived from structural magnetic resonance imaging scans using automated tissue segmentation. Analyses were performed separately in three cohorts with cross-sectional MRI data, a childhood/adolescent sample (NeuroIMAGE, 301 patients with ADHD and 186 healthy participants) and two adult samples (IMpACT, 118 patients with ADHD and 111 healthy participants; BIG, 1718 healthy participants). Regression analyses revealed that in the IMpACT cohort, and not in the other cohorts, carriers of the DAT1 adult ADHD risk haplotype 9-6 had 5.9 % larger striatum volume relative to participants not carrying this haplotype. This effect varied by diagnostic status, with the risk haplotype affecting striatal volumes only in patients with ADHD. An explorative analysis in the cohorts combined (N = 2434) showed a significant gene-by-diagnosis-by-age interaction suggesting that carriership of the 9-6 haplotype predisposes to a slower age-related decay of striatal volume specific to the patient group. This study emphasizes the need of a lifespan approach in genetic studies of ADHD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00702-016-1521-x) contains supplementary material, which is available to authorized users.

Substance use in young adults with ADHD: Comorbidity and symptoms of inattention and hyperactivity/impulsivity

Young adults with attention deficit hyperactivity disorder (ADHD) are at high risk of substance use (SU). The aims of the current study were: 1) to examine the use of alcohol, tobacco, marijuana and other illegal drugs by adults with and without ADHD; 2) to compare the oppositional, conduct, anxiety, depression, sleep and antisocial personality symptoms of ADHD adults with SU and ADHD adults without SU; 3) to examine the ability of ADHD symptoms and conduct problems to predict SU. A total of 93 young adults, 43 without ADHD and 50 with a childhood diagnosis of ADHD, who were part of the Spanish sample of the Multicenter ADHD Genetics (IMAGE) study, collaborated in a follow-up evaluation 10.1 years later. ADHD participants were divided into two groups based on the presence or absence of SU. Statistically significant differences were found between young adults with and without ADHD in their use of tobacco, marijuana and alcohol. A statistically significant association was also shown between externalization problems and a greater risk of SU. Conduct problems, to a greater degree than ADHD symptoms, affect SU in ADHD adults.

Dopamine and serotonin genetic risk scores predicting substance and nicotine use in attention deficit/hyperactivity disorder.

Individuals with attention deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence. The co-occurrence of ADHD and SUDs/nicotine dependence may in part be mediated by shared genetic liability. Several neurobiological pathways have been implicated in both ADHD and SUDs, including dopamine and serotonin pathways. We hypothesized that variations in dopamine and serotonin neurotransmission genes were involved in the genetic liability to develop SUDs/nicotine dependence in ADHD. The current study included participants with ADHD (n = 280) who were originally part of the Dutch International Multicenter ADHD Genetics study. Participants were aged 5-15 years and attending outpatient clinics at enrollment in the study. Diagnoses of ADHD, SUDs, nicotine dependence, age of first nicotine and substance use, and alcohol use severity were based on semi-structured interviews and questionnaires. Genetic risk scores were created for both serotonergic and dopaminergic risk genes previously shown to be associated with ADHD and SUDs and/or nicotine dependence. The serotonin genetic risk score significantly predicted alcohol use severity. No significant serotonin × dopamine risk score or effect of stimulant medication was found. The current study adds to the literature by providing insight into genetic underpinnings of the co-morbidity of ADHD and SUDs. While the focus of the literature so far has been mostly on dopamine, our study suggests that serotonin may also play a role in the relationship between these disorders.

DAT1 and DRD4 genes involved in key dimensions of adult ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3'UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p < 0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p = 0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p = 1.98 × 10(-4)) and trait anger scores (p = 7.66 × 10(-4)). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48-bp VNTR 6R allele and childhood maltreatment (p = 0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder.

P.1.k.020 Gender distribution, subtypes and other associated conditions of ADHD in school population aged 6–12 years – a cross sectional study

ADHD (Attention Deficit Hyperactivity Disorder) has a complex, heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6–18, participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding.

Neurocognitive predictors of substance use disorders and nicotine dependence in ADHD probands, their unaffected siblings, and controls: a 4-year prospective follow-up.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a risk factor for substance use disorders (SUDs) and nicotine dependence (ND). Neurocognitive deficits may predict the increased risk of developing SUDs and nicotine dependence. This study comprised three groups derived from the Dutch part of the International Multicenter ADHD Genetics (IMAGE) study: ADHD probands (n = 294), unaffected siblings (n = 161), and controls (n = 214). At baseline (age = 12.2), a range of neurocognitive functions was assessed including executive functions (inhibition, working memory, timing), measures of motor functioning (motor timing and tracking) and IQ. After a mean follow-up of 4.2 years, SUDs and ND were assessed. None of the neurocognitive functions predicted later SUDs or ND in ADHD probands, even after controlling for medication use and conduct disorder. Slower response inhibition predicted later nicotine dependence in unaffected siblings (OR = 2.06, 95% CI = 1.22-3.48), and lower IQ predicted increased risk for SUDs in controls (OR = 1.96, 95% CI = 1.12-3.44). Cold executive functions, motor functioning, and IQ did not predict the elevated risk of SUDs and ND in ADHD. Future studies should target 'hot' executive functions such as reward processing as risk factors for SUDs or ND.

The possible involvement of genetic variants of NET1 in the etiology of attention-deficit/hyperactivity disorder comorbid with oppositional defiant disorder.

Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) often coexist and shared some genetic influences. Evidence from the existing literature indicated that comorbid with ODD may increase the heterogeneity of ADHD genetics. Our present study sought to investigate the role of norepinephrine transporter gene (NET1) for ADHD comorbid with ODD. Six single nucleotide polymorphisms (SNPs) of NET1 were genotyped for a total of 1,815 ADHD cases, including 587 subjects (32.3%) with ODD. Chi-square tests were conducted for pseudo case-control study comparing allelic and genotypic distributions between ADHD with and without ODD. Among them, there were 1,249 probands together with their parents composing trios for family-based association studies using transmission disequilibrium tests (TDTs). In addition, 1,337 ADHD probands have detailed information of ODD symptoms and were included for quantitative analyses with genotypes using analyses of covariance (ANCOVA). To consider the overlap and correlation of other comorbidities with ODD and eliminate their potential confounding effect, we further repeated above analyses for 'pure ADHD+ODD' versus 'ADHD-only' after excluding other comorbidities except for ODD. The pseudo case-control study showed different allelic and genotypic distributions of SNP rs3785143 between ADHD with ODD and those without ODD. Family-based association tests indicated overtransmission of the T allele of rs3785143 in ADHD with ODD trios, but no biased transmission in those without ODD. ANCOVA showed association between genotypes of rs3785143 with ODD symptoms in ADHD probands, especially with 'Argumentative/Defiant Behavior (ADB)' dimension after controlling gender, age, clinical subtypes and intelligence. Above association still existed after removing the samples with other comorbidities. NET1 was associated with comorbidity of ODD and ODD symptoms in ADHD probands. Our findings emphasize the importance of considering the comorbidity of ODD in ADHD genetic studies, especially ADHD with ADB. However, further replication in independent sample or different populations is still needed.

Applying Imaging Genetics to ADHD: the Promises and the Challenges

Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent childhood psychiatric disorders. During the past decades, studies have focused on its genetic background and the abnormality of the brain structure and function. Recently, an advanced technique linking these two areas, namely, the imaging genetics emerged and kept growing. Imaging genetics primarily identifies genes that influence the brain variations. There are three main strategies of doing an imaging genetic study: using neuroimaging as endophenotypes to find the associated DNA variants, finding neuroimaging effects of risk genes, and hypothesis-free whole-brain voxelwise genome-wide association study. In this review, we begin with demonstrating the basic principles of imaging genetics precisely, with examples from other psychiatric conditions, and then go on to synthesize the existing imaging genetic studies in ADHD. Finally, we elaborate the challenges of applying imaging genetics to ADHD. We conclude that imaging genetics has somewhat showed its potential to provide a more precise understanding of how the genes shape the brain variations and further the clinical features of ADHD.

Genetics of Attention Deficit Hyperactivity Disorder (ADHD): Recent Updates and Future Prospects

Attention deficit hyperactivity disorder (ADHD) is not only highly prevalent, persistent and impairing but also is one of the most heritable of all psychiatric disorders. As a result, ADHD has been the focus of considerable genetic research. The results of recent genetic studies are reviewed with a focus on the emerging picture and future trends. ADHD appears to be a complex disorder in which multiple genetic and environmental risks contribute to a quantitative trait. At the same time, there is growing evidence that in a proportion of cases, individually rare variants such as copy number variants may play an important causal role. The more genetic risks, both common and rare, the more extreme the trait. With increasing samples and advanced genetic methods, single nucleotide polymorphism (SNPs) and copy number variants (CNVs) conferring risk for ADHD are being identified. Further study will be required before we can understand the causal significance of these findings. Increased sample size is an urgent necessity if we are to discover potentially causal variants. Non-behavioral markers of genetic risk known as endophenotypes could also play a role in parsing the phenotypic and genetic heterogeneity of ADHD as they have in other complex disorders. Genetic studies in ADHD hold the potential for refined nosology, more precise diagnosis, and differential diagnosis, improved early identification leading to novel intervention strategies and identification of innovative targets for therapeutics based on a precise understanding of disease mechanism.

ADHD Is a Risk Factor for Overweight and Obesity in Children

Although hyperactivity would seem to increase energy expenditure, attention-deficit hyperactivity disorder (ADHD) appears to increase the risk for being overweight. This study examined the body mass index (BMI) in children with ADHD and its relationship with age, gender, ADHD and comorbid symptom severity, inhibitory control, developmental coordination disorder, sleep duration, and methylphenidate use. Participants were 372 Dutch children with ADHD combined type aged 5 to 17 years participating in the International Multicenter ADHD Genetics (IMAGE) study. We categorized BMI according to international age- and gender-specific reference values and calculated BMI-standard deviation scores (BMI-SDS). The control population was matched for age, gender, and ethnicity and originated from the same birth cohort as the ADHD group. Inhibitory control was measured by the computerized Stop-signal task. Prevalence differences of underweight, overweight, and obesity between groups were expressed in odds ratios. We used linear regression analyses with gender, age, parent- and teacher-rated ADHD and comorbid scores, inhibitory control, sleep duration, motor coordination, and methylphenidate use to predict BMI-SDS. Boys with ADHD aged 10 to 17 years and girls aged 10 to 12 years were more likely to be overweight than children in the general Dutch population. Younger girls and female teenagers, however, seemed to be at lower risk for being overweight. Higher oppositional behavior and social communication problems related to higher BMI-SDS scores, whereas more stereotyped behaviors related to lower BMI-SDS scores. We found no effects of the other examined associated risk factors on BMI-SDS. Attention-deficit hyperactivity disorder in boys is a risk factor for overweight. In girls with ADHD, the prevalence of overweight is age dependent and most pronounced in girls aged 10 to 12 years. They have a 4-fold risk of being obese. Higher oppositional and social communication problems pose an increased risk for overweight, whereas sleep duration, motor coordination problems, and methylphenidate use do not.

Candidate Genetic Pathways for Attention-Deficit/Hyperactivity Disorder (ADHD) Show Association to Hyperactive/Impulsive Symptoms in Children With ADHD

Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD. The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neurotransmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales. Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms ((p)empirical = .007) but not with inattentive symptoms ((p)empirical = .73). Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result ((p)empirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, (p)empirical = .0004; serotonin, (p)empirical = .0149; neuritic outgrowth, (p)empirical = .0452). The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to identify biological risk factors involved in this disorder.

Association between SYP with attention-deficit/hyperactivity disorder in Chinese Han subjects: Differences among subtypes and genders

Dysfunction of neurotransmitters has been suggested to be involved in the etiology of attention-deficit/hyperactivity disorder (ADHD). Hence, genes encoding proteins involved in the vesicular release process of those neurotransmitters are attractive candidates in ADHD genetics. One of these genes is SYP, which encodes synaptophysin, a protein known to participate in regulating neurotransmitter release and synaptic plasticity. Several studies have reported an association between SYP and ADHD, but more work is needed to refine the association. In the present study, we attempt to investigate their association in Chinese Han subjects by family-based and case-control studies. Transmission disequilibrium tests (TDTs) in 1112 trios found significant association between SYP and the predominantly inattentive subtype (ADHD-I), especially for males with ADHD-I, both from single nucleotide polymorphism (SNP) and haplotypic analyses. Chi-square tests in 1682 ADHD probands and 957 comparison subjects indicated possible association of SYP with female ADHD and female ADHD-I. However, the associated alleles and haplotypes between males and females were reversed. In conclusion, our results suggested that SYP may be primarily associated with ADHD-I and its genetic mechanism may be gender-specific. Thus, it is necessary to take subtype and gender into account in ADHD genetic studies.

Substance use disorders in adolescents with attention deficit hyperactivity disorder: a 4-year follow-up study

To examine the relationship between a childhood diagnosis of attention deficit hyperactivity disorder (ADHD) with or without oppositional defiant disorder (ODD)/conduct disorder (CD) and the development of later alcohol/drug use disorder [psychoactive substance use disorder (PSUD)] and nicotine dependence in a large European sample of ADHD probands, their siblings and healthy control subjects. Subjects (n = 1017) were participants in the Belgian, Dutch and German part of the International Multicenter ADHD Genetics (IMAGE) study. IMAGE families were identified through ADHD probands aged 5-17 years attending out-patient clinics, and control subjects from the same geographic areas. After a follow-up period (mean: 4.4 years) this subsample was re-assessed at a mean age of 16.4 years. PSUD and nicotine dependence were assessed using the Diagnostic Interview Schedule for Children, Alcohol Use Disorders Identification Test, Drug Abuse Screening Test and Fagerström test for Nicotine Dependence. The ADHD sample was at higher risk of developing PSUD [hazard ratio (HR) = 1.77, 95% confidence interval (CI) = 1.05-3.00] and nicotine dependence (HR = 8.61, 95% CI = 2.44-30.34) than healthy controls. The rates of these disorders were highest for ADHD youth who also had CD, but could not be accounted for by this comorbidity. We did not find an increased risk of developing PSUD (HR = 1.18, 95% CI = 0.62-2.27) or nicotine dependence (HR = 1.89, 95% CI = 0.46-7.77) among unaffected siblings of ADHD youth. A childhood diagnosis of attention deficit hyperactivity disorder is a risk factor for psychoactive substance use disorder and nicotine dependence in adolescence and comorbid conduct disorder, but not oppositional defiant disorder, further increases the risk of developing psychoactive substance use disorder and nicotine dependence.

Rapid visual information processing as a cognitive endophenotype of attention deficit hyperactivity disorder

Deficits in sustained attention and reaction time are core features of attention deficit hyperactivity disorder (ADHD). However, little is known about attention performance in unaffected siblings. Hence, we examined sustained attention and reaction time in youths with ADHD, unaffected siblings and controls to test whether impaired performance in attention tasks can be a potential endophenotype of ADHD. We recruited 438 probands with clinical diagnosis of ADHD according to DSM-IV criteria, 180 unaffected siblings, and 173 healthy controls without lifetime ADHD. They were assessed using psychiatric interviews, Conners' Continuous Performance Test, and the tasks involving attention performance of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Rapid Visual Information Processing (RVP), Reaction Time (RTI) and Match to Sample Visual Search (MTS). Multi-level models were used for data analysis. Compared with the controls, probands with ADHD and unaffected siblings had significantly higher total misses, lower probability of hits in the RVP task and probands with ADHD performed worse in the RTI and MTS tasks after controlling for sex, age, co-morbidity, parental educational levels and IQ. The duration of methylphenidate use and IQ but not psychiatric co-morbidity or current use of methylphenidate were associated with deficits in sustained attention in probands with ADHD. Our findings suggest that attention performance assessed by the RVP task, but not the RTI or MTS tasks, of the CANTAB may be a useful cognitive endophenotype for ADHD genetic studies.

Correlations of gene expression with ratings of inattention and hyperactivity/impulsivity in tourette syndrome: a pilot study

BackgroundInattentiveness, impulsivity and hyperactivity are the primary behaviors associated with attention-deficit hyperactivity disorder (ADHD). Previous studies showed that peripheral blood gene expression signatures can mirror central nervous system disease. Tourette syndrome (TS) is associated with inattention (IA) and hyperactivity/impulsivity (HI) symptoms over 50% of the time. This study determined if gene expression in blood correlated significantly with IA and/or HI rating scale scores in participants with TS.MethodsRNA was isolated from the blood of 21 participants with TS, and gene expression measured on Affymetrix human U133 Plus 2.0 arrays. To identify the genes that correlated with Conners’ Parents Ratings of IA and HI ratings of symptoms, an analysis of covariance (ANCOVA) was performed, controlling for age, gender and batch.ResultsThere were 1201 gene probesets that correlated with IA scales, 1625 that correlated with HI scales, and 262 that correlated with both IA and HI scale scores (P<0.05, |Partial correlation (rp)|>0.4). Immune, catecholamine and other neurotransmitter pathways were associated with IA and HI behaviors. A number of the identified genes (n=27) have previously been reported in ADHD genetic studies. Many more genes correlated with either IA or HI scales alone compared to those that correlated with both IA and HI scales.ConclusionsThese findings support the concept that the pathophysiology of ADHD and/or its subtypes in TS may involve the interaction of multiple genes. These preliminary data also suggest gene expression may be useful for studying IA and HI symptoms that relate to ADHD in TS and perhaps non-TS participants. These results will need to be confirmed in future studies.

The role of a mineralocorticoid receptor gene functional polymorphism in the symptom dimensions of persistent ADHD

Attention-deficit/hyperactivity disorder (ADHD) affects approximately 5 % of school-aged children and 2.5 % of adults. Genetic studies in ADHD have pointed to genes in different neurobiological systems, with relatively small individual effects. The mineralocorticoid receptor is the main receptor involved in the initial triggering of stress response. Therefore, its encoding gene (NR3C2) is a candidate for psychiatric disorder studies, including ADHD, and behavioral phenotypes. There is evidence that the Val allele of the MRI180V polymorphism (rs5522) increases the risk of depression, attention and cognitive deficits. We investigated the possible role of the mineralocorticoid receptor gene in the symptom dimensions and susceptibility to persistent ADHD. We compared genotype and allele frequencies in 478 adult patients with ADHD and 597 controls and symptom dimensions in 449 patients and 132 controls. Diagnoses were based on the DSM-IV criteria. ADHD symptom dimensions were investigated with SNAP-IV for ADHD severity and Barkley scales for severity and impairment. Carriers of the Val allele presented higher inattention, hyperactivity/impulsivity and impairment scores, while genotype and allele frequencies did not differ between patients and controls. These results are consistent with a possible link between genetic variations in the HPA axis and inattention and hyperactivity measures.

Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder

Previous studies have suggested that there may be a parent-of-origin effect for attention-deficit/hyperactivity disorder(ADHD) candidate genes. The objective of the present study was to investigate parent-of-origin effects using a genome-wide association analysis of the International Multicentre ADHD Genetics (IMAGE) study sample. Family-based association analysis for ADHD using 846 ADHD probands and their parents was performed using the PLINK program, and parent-of-origin effects were studied using a Z score for the difference in paternal versus maternal odds ratios. We identified 44 single nucleotide polymorphisms (SNPs) showing parent-of-origin effects at a significance level of p < 0.001. The most significant SNP, rs7614907, is at position 3q13.33 in the CDGAP gene (p = 0.000064 for parent-of-origin effect). Furthermore, 2 genes (FAS and PDLIM1) showed moderate parent-of-origin effects (p = 0.00086 for rs9658691 and p = 0.00077 for rs11188249) and strong maternal transmission (p = 0.000059 for rs9658691 and p = 0.0000068 for rs11188249). In addition, ZNF775 showed a moderate parent-of-origin effect (p = 0.00036 for rs7790549) and strong paternal transmission (p = 0.000041 for rs7790549). We only had 1 sample available for analysis. These results suggest several genes or regions with moderate parent-of-origin effects, and these findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in ADHD.