Jacques Eisenberg

Family-based association study of the serotonin transporter promoter region polymorphism (5-HTTLPR) in attention deficit hyperactivity disorder

Low serotonin activity has been associated in both animal and human studies with measures of impulsivity, aggression, and disinhibited behaviors. Recently, a common 44-bp deletion in the promoter region of the serotonin transporter (5-HTTLPR) that results in reduced transcription and lower transporter protein levels was described. Toward unraveling a possible role of the 5-HTTLPR polymorphism in childhood disruptive behaviors, we examined this gene in attention deficit hyperactivity disorder (ADHD), a heterogeneous childhood disorder in which three phenotypes are recognized by DSM IV criteria: inattentive (type I), hyperactive-impulsive (type II), and combined type (type III). By using the haplotype relative risk design, a group of 98 triads (both parents and proband child) were tested for a possible association between 5-HTTLPR and ADHD. A significant decrease in the short/short 5-HTTLPR genotype was observed in the ADHD type III combined group (10.29% vs. 30.88%) compared with the HRR-derived control group (likelihood ratio = 9.62, P = 0.008, n = 68 triads). Similar results were observed when allele frequencies were compared (likelihood ratio = 3.81, P = 0.05, n = 136 alleles). These first findings should be interpreted cautiously until replicated in independently recruited clinical samples.

Haplotype relative risk study of catechol‐O‐methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): Association of the high‐enzyme activity val allele with adhd impulsive‐hyperactive phenotype

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Both environmental and genetic factors contribute to the etiology of this complex disease. In the current investigation, a catechol-O-methyltransferase (COMT) polymorphism that codes for a high versus low enzyme COMT activity was examined using family-based methods for a role in ADHD. Using a haplotype relative risk design and a parent-to-proband allele transmission test with 48 ADHD triads, we found an association between COMT and illness (chi(2) = 4.72, p = 0.03, df = 1). In particular, the impulsive-hyperactive type of ADHD (excluding inattention) ascertained by Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria (chi(2) = 8.34, p = 0.004, df = 1), by the Conners Teaching Rating Hyperactivity scale (Pearson chi(2) = 5.32, p = 0.02, df = 1) as well as by the Continuous Performance Test False Alarm scale (chi(2) = 2.78, p = 0.096, df = 1) were associated with the high enzyme activity COMT val allele. Similar results were obtained if genotype frequencies were compared. It should be noted that the association between the high-enzyme activity COMT val allele that increases CNS dopamine (and norepinephrine) clearance is consistent with the use of methylphenidate, an agent that increases dopamine (and norepinephrine) turnover, in the treatment of this disorder. These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinsons disease, might in due time be considered in the treatment of ADHD.

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.

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.

Failure to replicate an excess of the long dopamine D4 exon III repeat polymorphism in ADHD in a family-based study

The DRD4 exon III repeat polymorphism has been associated in adults with Novelty Seeking personality traits and in children with attention deficit hyperactivity disorder (ADHD) in some but not all studies. In a previous report we failed to observe preferential transmission of the long DRD4 repeat in ADHD compared to the haplotype relative risk (HRR) derived control group in a group of 49 triads (both parents and ADHD child) recruited in the Jerusalem area. In the current study we independently recruited an additional group of 49 triads from a different geographical location (Petak Tikvah) in Israel but having a similar ethnic background. In contrast to previous findings from a number of groups, in the current study an excess of the long DRD4 alleles was observed in the HRR control group compared to the ADHD subjects (Likelihood ratio = 5.50, P = 0. 02). In the expanded Israeli group of 98 triads so-far examined for the DRD4 repeat polymorphism there is an excess of the long alleles in the HRR control group (Likelihood ratio = 3.81, P = 0.05). These results attest to the complexity of ADHD inheritance and the likelihood that genetic heterogeneity characterizes this disorder especially across ethnic and cultural boundaries.

A haplotype relative risk study of the dopamine D4 receptor (DRD4) exon III repeat polymorphism and attention deficit hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Several investigations have recently examined the role of the dopamine DRD4 exon III repeat polymorphism in ADHD. The long 7 repeat allele of this receptor was shown in three family-based studies, but not in one case control design, to be a risk factor for this disorder. We now report an additional family-based study of DRD4 exon III repeat region and ADHD. However, in the current study we fail to observe preferential transmission of the DRD4 exon III long 7 repeat allele, chi(2) = 0. 142, P < 0.1, df = 1. Nor was any preferential transmission observed when genotypes were compared, chi(2) = 0.180, P > 0.1, df = 1. Possible reasons are discussed, especially lack of sufficient power in analying more refined phenotypes, why the current results in contrast to previous findings fail to support a role for the long form of the DRD4 receptor as a putative risk factor for ADHD.

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).

The hierarchical factor model of ADHD: invariant across age and national groupings?

OBJECTIVE To examine the factor structure of attention-deficit/hyperactivity disorder (ADHD) in a clinical sample of 1,373 children and adolescents with ADHD and their 1,772 unselected siblings recruited from different countries across a large age range. Hierarchical and correlated factor analytic models were compared separately in the ADHD and sibling samples, across three different instruments and across parent and teacher informants. Specific consideration was given to factorial invariance analyses across different ages and different countries in the ADHD sample. METHOD A sample of children and adolescents between 5 and 17 years of age with ADHD and their unselected siblings was assessed. Participants were recruited from seven European countries and Israel. ADHD symptom data came from a clinical interview with parents Parental Account of Childhood Symptoms and questionnaires from parents and teachers (Conners Parent and Teacher). RESULTS A hierarchical general factor model with two specific factors best represented the structure of ADHD in both the ADHD and unselected sibling groups, and across informants and instruments. The model was robust and invariant with regard to age differences in the ADHD sample. The model was not strongly invariant across different national groups in the ADHD sample, likely reflecting severity differences across the different centers and not any substantial difference in the clinical presentation of ADHD. CONCLUSIONS The results replicate previous studies of a model with a unitary ADHD component and separable specific traits of inattention and hyperactivity/impulsivity. The unique contribution of this study was finding support for this model across a large developmental and multinational/multicultural sample and its invariance across ages.

Association of the dopamine D5 receptor with attention deficit hyperactivity disorder (ADHD) and scores on a continuous performance test (TOVA).

Towards further clarifying the role of dopamine D5 receptor (DRD5) microsatellite polymorphism in the etiology of ADHD, we used a robust family based strategy to test for association between DRD5 and this disorder. Additionally, a neuropsychological mechanism by which this allele may confer risk was explored by examining the relationship between DRD5 genotype and scores on a continuous performance test. DNA was obtained from 164 probands and their parents. Additionally, the majority of these probands were administered a computerized continuous performance test, the Test Of Variables of Attention (TOVA). We first confirmed preferential transmission (TDT χ2 = 7.02, P = 0.008) of the 148 base pair allele in 155 informative transmissions (94 transmitted and 61 non‐transmitted 148 bp allele). Additionally, we used a family‐based association test (FBAT) and observed significant multivariate association using FBAT between TOVA scores before methylphenidate administration and the DRD5 microsatellite polymorphism across all four TOVA variables: multi‐allelic, multivariate test χ2 = 16.32, P = 0.037 when the 148 bp allele was compared to all others (collapsed genotype) that was also significant (χ2 = 59.20, P = 0.025) when all 14 alleles (full genotype) were analyzed. Following methylphenidate, no significant association was observed (χ2 = 12.08, P = 0.147 for 148 bp versus all others) and, similarly, for all 14 alleles (χ2 = 47.18, P = 0.343). In summary, the main finding of this report is that the DRD5 repeat polymorphism confers a small but significant risk for ADHD consistent with previous reports. Provisional results in this single investigation suggest that the DRD5 microsatellite also affects performance scores on the TOVA.