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Showing papers by "Stephen V. Faraone published in 2005"


Journal ArticleDOI
TL;DR: Difficulties with EF appear to be one important component of the complex neuropsychology of ADHD, and moderate effect sizes and lack of universality of EF deficits among individuals with ADHD suggest that EF weaknesses are neither necessary nor sufficient to cause all cases of ADHD.

3,155 citations


Journal ArticleDOI
TL;DR: Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD, and seven genes for which the same variant has been studied in three or more case-control or family-based studies show statistically significant evidence of association with ADHD.

2,087 citations


Journal ArticleDOI
TL;DR: The results show that estimates of ADHD's persistence rely heavily on how one defines persistence, yet, regardless of definition, the analyses show that evidence for ADHD lessens with age.
Abstract: Background. This study examined the persistence of attention deficit hyperactivity disorder (ADHD) into adulthood.Method. We analyzed data from published follow-up studies of ADHD. To be included in the analysis, these additional studies had to meet the following criteria: the study included a control group and it was clear from the methods if the diagnosis of ADHD included subjects who did not meet full criteria but showed residual and impairing signs of the disorder. We used a meta-analysis regression model to separately assess the syndromatic and symptomatic persistence of ADHD.Results. When we define only those meeting full criteria for ADHD as having ‘persistent ADHD’, the rate of persistence is low, ~15% at age 25 years. But when we include cases consistent with DSM-IV's definition of ADHD in partial remission, the rate of persistence is much higher, ~65%.Conclusions. Our results show that estimates of ADHD's persistence rely heavily on how one defines persistence. Yet, regardless of definition, our analyses show that evidence for ADHD lessens with age. More work is needed to determine if this reflects true remission of ADHD symptoms or is due to the developmental insensitivity of diagnostic criteria for the disorder.

1,849 citations


Journal ArticleDOI
16 Jul 2005
TL;DR: Converging evidence from animal and human studies implicates the dysregulation of frontal-subcortical-cerebellar catecholaminergic circuits in the pathophysiology of ADHD, and molecular imaging studies suggest that abnormalities of the dopamine transporter lead to impaired neurotransmission.
Abstract: Attention-deficit hyperactivity disorder (ADHD) is a disorder of inattention, impulsivity, and hyperactivity that affects 8-12% of children worldwide. Although the rate of ADHD falls with age, at least half of children with the disorder will have impairing symptoms in adulthood. Twin, adoption, and molecular genetic studies show ADHD to be highly heritable, and other findings have recorded obstetric complications and psychosocial adversity as predisposing risk factors. Converging evidence from animal and human studies implicates the dysregulation of frontal-subcortical-cerebellar catecholaminergic circuits in the pathophysiology of ADHD, and molecular imaging studies suggest that abnormalities of the dopamine transporter lead to impaired neurotransmission. Studies during the past decade have shown the safety and effectiveness of new non-stimulant drugs and long-acting formulations of methylphenidate and amfetamine. Other investigations have also clarified the appropriate role of targeted psychosocial treatments in the context of ongoing pharmacotherapy.

1,356 citations



Journal ArticleDOI
TL;DR: It is suggested that adult ADHD is a common disorder associated with impaired functioning and having ADHD is associated with lower levels of education and employment status.
Abstract: To provide a better estimate of the prevalence of ADHD in adulthood, the authors complete a telephone survey of 966 randomly selected adults. They compute two diagnoses from the survey data. Participants meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria for both childhood and adulthood are defined as narrow ADHD. Broad ADHD adds to that definition those meeting subthreshold criteria. Cronbach's alpha is .90 for the 18 DSM-IV symptoms in childhood and .88 when rated for current symptoms in adulthood. No one item unduly influences the reliability of the total score. The authors find similar results in separate analyses of hyperactive-impulsive and inattentive symptoms. They estimate prevalences of 2.9% for Narrow ADHD and 16.4% for Broad ADHD. Having ADHD is associated with lower levels of education and employment status. These findings suggest that adult ADHD is a common disorder associated with impaired functioning.

493 citations


Journal ArticleDOI
TL;DR: Promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELn gene hypoactivity in schizophrenia, according to the small sample size.
Abstract: DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol–chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73% of the trials (16 of 22) in schizophrenic patients compared with 24% (5 of 21) of controls. Thus, the hypermethylation of the CpG islands flanking a CRE and SP1 binding site observed at a significantly higher level (t = −5.07, P = 0.001) may provide a mechanism for the decreased RELN expression, frequently observed in post-mortem brains of schizophrenic patients. We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR. Despite the small sample size, these studies indicate that promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELN gene hypoactivity in schizophrenia. Further studies with a larger sample set would be required to validate these preliminary observations. © 2005 Wiley-Liss, Inc.

382 citations


Journal ArticleDOI
TL;DR: A marked therapeutic response for the MPH treatment of ADHD symptoms that exceeded the placebo response was found and robust doses of MPH are effective in the treatment of adult ADHD.

342 citations


Journal ArticleDOI
TL;DR: Although there is fair agreement regarding the presence and direction of abnormal DAT binding, there remains disagreement as to the magnitude of the finding and the importance of many potentially confounding variables, including clinical characteristics and imaging methodology.

304 citations


Journal ArticleDOI
TL;DR: The findings suggest that the clinical correlates of ADHD are not influenced by gender and that gender differences reported in groups of subjects seen in clinical settings may be caused by referral biases.
Abstract: OBJECTIVE: In a previous study, the authors found that, compared with referred boys with attention deficit hyperactivity disorder (ADHD), girls are less likely to manifest comorbid disruptive behavior disorders and learning disabilities—characteristics that could adversely affect identification of ADHD in girls. However, because referral bias can affect outcome, these findings require replication in nonreferred groups of ADHD subjects. METHOD: The authors evaluated gender effects in a large group of nonreferred siblings (N=577) of probands with ADHD and non-ADHD comparison subjects. Ninety-eight of the nonreferred siblings (N=73 males, N=25 females) met the criteria for diagnosis of ADHD, and 479 (N=244 males, N=235 females) did not meet those criteria. All siblings were systematically and comprehensively assessed with measures of emotional, school, intellectual, interpersonal, and family functioning. The assessment battery used for the siblings was the same as that used for the probands. RESULTS: The non...

279 citations


Journal ArticleDOI
TL;DR: The small but significant effects of the 44‐bp insertion/deletion polymorphism for BP is consistent with being one of many genes that contributes to the multi‐factorial nature of these psychiatric disorders.
Abstract: Family, twin, and adoption studies show that psychiatric diseases including bipolar disorder (BP) and unipolar disorder (UP) have a substantial genetic component. For these illnesses, both positive and negative associations have been reported for two polymorphisms located in the serotonin transporter gene (5-HTT) on chromosome 17: a 17-base-pair (bp) variable-number tandem-repeat (VNTR) in intron 2 and a 44-bp insertion/deletion in the promoter region. Thus, associations between these 5-HTT polymorphisms and affective disorders remain unclear. The present work investigates these potential associations in meta-analyzes that maximize the power to find associations between each disease and the two 5-HTT polymorphisms. We applied meta-analysis techniques to case-control studies of two 5-HTT polymorphisms and two affective disorders (BP and UP), resulting in four meta-analyzes. For each polymorphism, we assessed the evidence for allelic associations, heterogeneity among studies, the influence of individual studies, and the potential for publication bias. The short allele(s) of the 44-bp insertion/deletion polymorphism showed a significant association for BP (odds ratio (OR) = 1.13, P = 0.001) but not UP. For the 17-bp VNTR, an increase in the number of tandem repeats had no significant association with any of the disorders. The small but significant effects of the 44-bp insertion/deletion polymorphism for BP is consistent with being one of many genes that contributes to the multi-factorial nature of these psychiatric disorders. © 2004 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: It is demonstrated that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease, and genomewide significant linkage to BP on chromosomes 6q and 8q is established.
Abstract: Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

Journal ArticleDOI
TL;DR: Existing data on potential endophenotypes for ADHD are reviewed, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement, and it is concluded that these endophenotype will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power.

Journal ArticleDOI
TL;DR: Evidence supporting the use of deficits on neurocognitive measures of executive functions for ADHD is reviewed and empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD are discussed.
Abstract: Background: Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or phenotypes that are more closely linked to the neurobiological substrate of a disorder, offer the potential to address these two issues simultaneously (Freedman, Adler, & Leonard, 1999). Thus far, potential endophenotypes for ADHD have not been systematically studied. Method: The current paper reviews evidence supporting the use of deficits on neurocognitive measures of executive functions for this purpose. Results: Such deficits are a correlate of ADHD and show preliminary evidence of heritability and association with relevant candidate genes. Nonetheless, studies that have assessed the familial and genetic overlap of neurocognitive impairments with ADHD have yielded inconsistent results. Conclusions: In order for executive function deficits to be used as an endophenotype for ADHD, we recommend greater attention to the neurocognitive heterogeneity of this disorder and to the precision of measurement of the neuropsychological tests employed. We also discuss empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD.

Journal ArticleDOI
TL;DR: The findings suggest that the cerebellum is involved in the pathophysiology of at least some cognitive deficits associated with ADHD and emphasize the need for additional research aimed at elucidating the role of the Cerebellum in ADHD symptomatology.

Journal ArticleDOI
TL;DR: It is suggested that executive dysfunctions are correlates of ADHD regardless of gender and age, at least through the late teen years, and these impairments are found at ages 9 to 12 and ages 13 to 17.
Abstract: ADHD is known to have neuropsychological correlates, characterized mainly by executive function (EF) deficits. However, most available data are based on studies of boys through age 12. Our goal was to assess whether girls with ADHD express neuropsychological features similar to those found in boys, and whether these impairments are found in both preteen and teen samples. Participants were 101 girls and 103 boys with DSM-III-R ADHD, and 109 comparison girls and 70 boys without ADHD, ages 9 to 17 years. Information on neuropsychological performance was obtained in a standardized manner blind to clinical status. Primary regression analyses controlled for age, socioeconomic status, learning disability, and psychiatric comorbidity. Girls and boys with ADHD were significantly more impaired on some measures of EFs than healthy comparisons but did not differ significantly from each other. With the exception of 1 test score there were no significant Sex x Diagnosis interactions. Moreover, there were no more significant interactions among age, gender, and diagnosis than would be expected by chance. Neuropsychological measures of EFs were comparably impaired in girls compared to boys with ADHD, and these impairments are found at ages 9 to 12 and ages 13 to 17. These findings suggest that executive dysfunctions are correlates of ADHD regardless of gender and age, at least through the late teen years.

Journal ArticleDOI
TL;DR: Findings are consistent with prior findings of hypofrontality in ADHD children and implicate a compensatory network including basal ganglia, insula and cerebellum for relative lower cognitive load tasks.
Abstract: Using event-related functional magnetic resonance imaging to study the Stroop, effect on both behavioral and brain activation of ADHD children off or on methylphenidate (MPH). Nine ADHD boys (aged 9.8-14.5 years) and 9 age-matched normal controls were included. A Stroop-like paradigm was used. AFNI (Analysis of Functional Neurolmaging) and its Deconvolution Analysis were used in a descriptive comparison between ADHD and control groups. (1) Both behavioral reaction time and brain activation showed Stroop effect in controls but neither was found in ADHD children off MPH. When MPH was administered, the Stroop effect tended to appear. (2) The activation volume (AV) of prefrontal cortex (PFC) in both the neutral (NC) and interference conditions (IQ in ADHD children off MPH was smaller than in controls. AV of anterior cingulate cortex in the IC in ADHD children off MPH was smaller than that in controls, but was similar in the NC to that in controls. AV of the basal ganglia, insula and cerebellum was also smaller in the IC, but was larger in the NC for ADHD children off MPH compared with controls. These findings are consistent with prior findings of hypofrontality in ADHD children and implicate a compensatory network including basal ganglia, insula and cerebellum for relative lower cognitive load tasks. (c) 2005 Elsevier B.V. All rights reserved.

Journal ArticleDOI
TL;DR: Results suggest that the CRH gene influences inhibited temperament, a risk factor for panic and phobic anxiety disorders, in children at risk for panic disorder.

Journal ArticleDOI
TL;DR: Data support a modest neuropsychological deficit in persons at genetic HR for psychosis, with a broader range of deficits in HR-SCZ, and future work should assess the relationship of neurocognition to adaptive functioning and possible onset of psychosis in HR samples.
Abstract: Siblings and offspring of persons with schizophrenia carry elevated genetic risk for the illness and manifest attentional and memory impairments. Because less is known about other neuropsychological functions and their specificity in adolescents, we conducted a genetic high-risk (HR) study of schizophrenia (HR-SCZ) and affective psychosis (HR-AFF). Participants (ages 12-25) were from the Harvard Adolescent High-Risk and Hillside Family studies, including 73 HR-SCZ, 18 HR-AFF, and 84 community controls (CCs) recruited in metropolitan Boston and New York. Groups were compared on overall neurocognitive functioning, 6 domains, and 13 test scores, controlling for age, parental education, and correlated data within families. The HR-SCZ group was significantly impaired overall, while the HR-AFF group demonstrated a trend toward overall impairment. HR-SCZ subjects showed significantly lower Verbal Ability (d = .73) and Executive Functioning/Working Memory (d = .47) than CCs. HR-AFF subjects showed reduced Verbal Ability (d = .64) compared to CCs. Excluding 12 CCs with a parental history of depression (without psychosis) led to larger differences between HR and CC groups across domains. Moreover, HR-SCZ and CC group differences in Verbal Memory (d = .39) and Visual-Spatial (d = .34) became statistically significant. There were no significant differences between HR-SCZ and HR-AFF groups. Data support a modest neuropsychological deficit in persons at genetic HR for psychosis, with a broader range of deficits in HR-SCZ. Future work should assess the relationship of neurocognition to adaptive functioning and possible onset of psychosis in HR samples. Ascertainment criteria for controls may markedly influence results and interpretation of group differences.

Journal ArticleDOI
TL;DR: After controlling for ADHD, youth with BPD show neuropsychological deficits similar to impairments found in adults with the disorder, associated with impairments on subtests reflecting sustained attention, working memory, and processing speed.

01 Jan 2005
TL;DR: A comprehensive review of existing imaging studies of DAT binding in ADHD shows that six of eight independent studies by six different groups have reported increased binding in (mostly) treatment-naive children and adults with ADHD.
Abstract: There is converging evidence of the role of catecholamine dysregulation in the underlying pathophysiology of attention-deficit/ hyperactivity disorder (ADHD). The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent genetic, treatment, and imaging studies have highlighted the role of DAT in ADHD. There is an emerging literature on in vivo neuroreceptor imaging of DAT in ADHD and control subjects reported by a number of groups internationally. A comprehensive review of existing imaging studies of DAT binding in ADHD shows that six of eight independent studies by six different groups have reported increased DAT binding in (mostly) treatment-naive children and adults with ADHD. Although there is fair agreement regarding the presence and direction of abnormal DAT binding, there remains disagreement as to the magnitude of the finding and the importance of many potentially confounding variables, including clinical characteristics and imaging methodology. Three studies by three different groups have reported decreased DAT binding after methylphenidate treatment. Interpretation of the latter finding awaits clarification of the issue of timing of drug administration and imaging to disentangle receptor occupancy from downregulation.

Journal ArticleDOI
TL;DR: The consistency of clinical features of bipolar disorder seen across age groups (children vs. adolescents) and cohorts (early and late cohorts) over the past decade supports the hypothesis that BPD in the young is a severe condition afflicting a sizeable minority of referred youth.

Journal ArticleDOI
TL;DR: A large population-based twin sample is used to evaluate the prevalence and genetic architecture of the CBCL-JBD (deviant on AP, AGG, and AD) phenotype and compare these data to children who are deviant on just theCBCL-AP syndrome.

Journal ArticleDOI
TL;DR: Evidence is presented to show that ADHD meets the criteria for a valid psychiatric diagnosis and has a biological basis and a characteristic response to treatment, which support the idea that ADHD is a valid diagnostic category.
Abstract: Continued questioning of the validity of a diagnosis of attention-deficit/hyperactivity disorder (ADHD) has created uncertainties about its management in the minds of many clinicians and the public. Inaccurate beliefs about the validity of ADHD hinder the clinical care of many ADHD patients and lead to confusion about the need to seek out or accept treatment. Critics describe ADHD as a diagnosis used to label difficult children who are not ill but whose behavior is at the extreme end of normal. They further contend that, far from having a biological basis, ADHD results from poor parenting and ineffective teaching practices. Such attitudes do much to further stigmatize patients and their families and increase the burden of this debilitating condition. This review attempts to address these challenges by presenting evidence to show that ADHD meets the criteria for a valid psychiatric diagnosis. Not only does it cause specific disabling symptoms that frequently persist into adulthood, but many studies show it has a biological basis and a characteristic response to treatment. Such data support the idea that ADHD is a valid diagnostic category.

Journal ArticleDOI
TL;DR: Findings suggest that the CBCL-PBD may provide a highly efficient way of screening for childhood bipolar disorder.
Abstract: Background: No clear consensus has been reached yet on how best to characterize children who suffer from pediatric bipolar disorder (PBD). The CBCL-PBD profile on the Child Behavior Checklist (CBCL) has been consistently reported showing deviant findings on the Attention Problems, Aggressive Behavior, and Anxious-Depressed subscales. Aim: To examine the sensitivity and specificity of the proposed CBCL-PBD profile for determining DSM diagnosis of PBD. Methods: We applied receiver operating characteristic (ROC) curve analysis to data from 471 probands from two family studies of attention-deficit hyperactivity disorder and their 410 siblings. Results: The CBCL-PBD score demonstrated an area under the curve (AUC) of 0.97 for probands and 0.82 for siblings for current diagnosis of PBD, suggesting that the CBCL-PBD provided a highly efficient way of identifying subjects with a current diagnosis of PBD in this sample. Conclusions: These findings suggest that the CBCL-PBD may provide a highly efficient way of screening for childhood bipolar disorder.

Journal ArticleDOI
TL;DR: The partial unlinking of symptoms and impairment has implications for decisions about the diagnostic process, research criteria for participant inclusion, prevalence estimates, gender ratios, evaluation of treatment effects, service delivery, and many other issues.
Abstract: Diagnosing ADHD based primarily on symptom reports assumes that the number/frequency of symptoms is tied closely to the impairment imposed on an individual's functioning. That presumed linkage encourages diagnosis more by Diagnostic and Statistical Manual of Mental Disorders (4th ed.) style symptom lists than well-defined, psychometrically sound assessments of impairment. The current study correlated measures reflecting each construct in four separate, large-scale ADHD research samples. Average correlation between symptoms and impairment accounted for less than 10% of variance. Symptoms never predicted more than 25% of the variance in impairment. When an ADHD group was formed according to a measure of current symptoms, the sample size shrunk by 77% when a criterion-based measure of impairment was added. The partial unlinking of symptoms and impairment has implications for decisions about the diagnostic process, research criteria for participant inclusion, prevalence estimates, gender ratios, evaluation of treatment effects, service delivery, and many other issues.

Journal ArticleDOI
TL;DR: These findings support the clinical relevance of severe irritability as the most common presentation of mania in the young and support the use of unmodified DSM-IV criteria in establishing the diagnosis ofMania in pediatric populations.

Journal ArticleDOI
TL;DR: The utility of the CBCL as a screening tool for the identification of psychiatric comorbidity in ADHD youth in the primary care setting is supported, and good convergence between structured interview diagnoses and syndrome congruent CBCL scales is observed.
Abstract: Aims: To examine the informativeness of the Child Behavior Checklist (CBCL) as a screening tool to identify comorbid and non-comorbid cases of attention deficit hyperactivity disorder (ADHD) in a paediatrically referred population. It was hypothesised that specific scales of the CBCL would help identify specific comorbidities within ADHD cases in the primary care setting. Methods: The sample consisted of children and adolescents 6–17 years old of both genders with ADHD (n = 121). A receiver operating curve (ROC) approach was used to determine which CBCL scales best differentiated between ADHD cases with and without its comorbidities with conduct, anxiety, and mood disorders. Results: ROC analysis showed that the CBCL Delinquent Behavior and Aggressive Behavior scales predicted the structured interview derived diagnoses of conduct and bipolar disorder, the Anxious/Depressed and Aggressive Behavior scales predicted major depression, and the Anxious/Depressed and Attention problems scales predicted anxiety disorders. Conclusions: These results extend to a paediatrically referred population with previously reported findings in psychiatric samples documenting good convergence between structured interview diagnoses and syndrome congruent CBCL scales. These findings support the utility of the CBCL as a screening tool for the identification of psychiatric comorbidity in ADHD youth in the primary care setting.

Journal ArticleDOI
TL;DR: It is concluded that atomoxetine is an effective treatment for ADHD among adults when evaluated using several criteria.
Abstract: Background The objective of this study was to evaluate the efficacy of atomoxetine, a new and highly selective inhibitor of the norepinephrine transporter, in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) among adults by using drug-placebo response curve methods.

Journal ArticleDOI
TL;DR: Use of alternative population-based defined ADHD subtypes may help resolve some of the variable results presented for candidate gene association studies in ADHD.
Abstract: Background: It has been proposed that some of the variability in reporting of associations between attention deficit hyperactivity disorder (ADHD) and candidate genes may result from mixing of genetically heterogeneous forms of ADHD using DSM-IV criteria. The goal of the current study is to test whether population-based ADHD subtypes defined by latent class analysis help resolve issues of variable findings across individual gene association studies. Methods: Three studies which had previously reported no associations between polymorphisms of the DRD4 and DAT genes and DSM-IV defined ADHD were reanalyzed using population-based and DSM-IV defined ADHD subtypes. Results: Across studies no significant associations were found for either DRD4 or DAT polymorphisms using DSM-IV ADHD subtypes. In contrast, a significant association was found between the combined data set for the 440 base pair 3¢ DAT VNTR polymorphism and population-defined severe combined ADHD (OR ¼ 1.25, p ¼ .01). A marginally significant association was also found between the 7 repeat DRD4 allele and population-defined severe combined ADHD. Conclusion: Use of alternative population-based defined ADHD subtypes may help resolve some of the variable results presented for candidate gene association studies in ADHD. Keywords: Attention deficit/hyperactivity disorder, DRD4, DAT, latent class analysis. Abbreviations: ADHD: attention deficit/hyperactivity disorder; VNTR: variable number of tandem repeats; DRD4: dopamine D4 receptor gene; DAT: dopamine transporter gene; TDT: transmission disequilibrium test.