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Showing papers by "Stephen V. Faraone published in 2011"


Journal ArticleDOI
TL;DR: These findings prospectively confirm that persistence of ADHD over the long term is predictable from psychosocial adversity and psychiatric comorbidity ascertained 11 years earlier.

336 citations


Journal ArticleDOI
TL;DR: Predictive scores show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts, with implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.
Abstract: There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.

172 citations


Journal ArticleDOI
TL;DR: Cognitive behavioral interventions have proven popular in the treatment of adult ADHD, especially within the adult population who cannot or will not use medications, along with the many medication-treated patients who continue to show residual disability.
Abstract: Attention deficit hyperactivity disorder (ADHD) is a neurocognitive behavioral developmental disorder most commonly seen in childhood and adolescence, which often extends to the adult years. Relative to a decade ago, there has been extensive research into understanding the factors underlying ADHD, leading to far more treatment options available for both adolescents and adults with this disorder. Novel stimulant formulations have made it possible to tailor treatment to the duration of efficacy required by patients, and to help mitigate the potential for abuse, misuse and diversion. Several new non-stimulant options have also emerged in the past few years. Among these, cognitive behavioral interventions have proven popular in the treatment of adult ADHD, especially within the adult population who cannot or will not use medications, along with the many medication-treated patients who continue to show residual disability.

155 citations


Journal ArticleDOI
TL;DR: Adults with ADHD have subtle volume reductions in the caudate and possibly other brain regions involved in attention and executive control supporting frontostriatal models of ADHD.

147 citations


Journal ArticleDOI
TL;DR: The pattern of inheritance of ADHD with DESR preliminarily suggests that DESR may be a familial subtype of ADHD, and the data suggest thatDESR is not an expression of other axis I DSM-IV disorders or of nonfamilial environmental factors.
Abstract: Objective:A growing body of research suggests that deficient emotional self-regulation (DESR) is prevalent and morbid among patients with attention deficit hyperactivity disorder (ADHD). Family studies provide a method of clarifying the co-occurrence of clinical features, but no family studies have yet addressed ADHD and DESR. Method:Participants were 83 probands with and without ADHD and 128 siblings. All were assessed for axis I DSM-IV conditions with structured diagnostic interviews. The authors defined DESR in adult probands and siblings using items from the Barkley Current Behavior Scale. Analyses tested hypotheses about the familial relationship between ADHD and DESR. Results:Siblings of ADHD probands were at elevated risk of having ADHD, irrespective of the presence or absence of DESR in the proband. The risk for DESR was elevated in siblings of ADHD plus DESR probands but not in siblings of ADHD probands. ADHD and DESR cosegregated in siblings. The risk for other psychiatric disorders was similar ...

118 citations


10 Aug 2011
TL;DR: Examining single-nucleotide polymorphisms spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1.
Abstract: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

109 citations


Journal ArticleDOI
TL;DR: The epidemiology of ADHD in French children is similar to the epidemiology in other countries, and the well-known association of ADHD with CD, ODD, and indices of school failure is replicated.
Abstract: Background: Earlier studies point to the prevalence of attention deficit hyperactivity disorder (ADHD) to be similar around the world. There is, however, a wide variety in estimates. The prevalence of ADHD in youth has never been examined in France. Method: Starting with 18 million telephone numbers, 7,912 numbers are randomly selected. Among the 4,186 eligible families, 1,012 (24.2%) are successfully recruited. A telephone interview is administered to all families about a child in the 6 to 12 age range. It covered family living situation, school performance, symptoms of ADHD, conduct disorder (CD), and oppositional-defiant disorder (ODD), and other features of ADHD. Results: The prevalence of ADHD in France is between 3.5% and 5.6%. The population prevalence of treatment for ADHD is 3.5%. ADHD youth are more likely to be men than women, and, compared to non-ADHD children, ADHD children are more likely to have CD and ODD. Having ADHD is associated with a family history of the disorder. The ADHD youth are ...

109 citations


Journal ArticleDOI
TL;DR: More work is needed to assess the safety and efficacy of psychotropic drugs in children younger than 10 years, to further evaluation the efficacy of naturopathic compounds, and to further evaluate the effects of antimanic treatments for the management of depression and attention-deficit/hyperactivity disorder.
Abstract: Objective A growing body of literature has documented pediatric bipolar disorder to be a severely impairing form of psychopathology. However, concerns remain as to the inadequacy of the extant literature on its pharmacotherapy. Furthermore, treatment studies have not been systematically reviewed for treatment effects on core and associated symptoms. Thus, a systematic evaluation and synthesis of the available literature on the efficacy of antimanic pharmacotherapy for pediatric bipolar disorder on symptoms of mania, depression, and attention-deficit/hyperactivity disorder was undertaken. Method A systematic search was conducted through PubMed from 1989 through 2010 for open-label and randomized controlled trials published in English on the pharmacotherapy of pediatric mania. Results There have been 46 open-label ( n = 29) and randomized ( n = 17) clinical trials of antimanic agents in pediatric bipolar disorder encompassing 2,666 subjects that evaluated a range of therapeutic agents, including traditional mood stabilizers, other anticonvulsants, second-generation antipsychotics, and naturopathic compounds. This literature has documented that the available armamentarium has different levels of efficacy in the treatment of pediatric mania. Because all psychotropic classes are associated with important adverse effects, a careful risk-benefit analysis is warranted when initiating pharmacologic treatment with any of these compounds. In the limited data available, the effects of antimanic agents on depression and symptoms of attention-deficit/hyperactivity disorder have been, in general, modest. Few studies have evaluated the effects of antimanic agents in children younger than 10 years. Conclusions A substantial body of scientific literature has evaluated the safety and efficacy of various medicines and drug classes in the treatment of mania in pediatric bipolar disorder. More work is needed to assess the safety and efficacy of psychotropic drugs in children younger than 10 years, to further evaluate the efficacy of naturopathic compounds, and to further evaluate the effects of antimanic treatments for the management of depression and attention-deficit/hyperactivity disorder.

103 citations


Journal ArticleDOI
TL;DR: The CBCL-DESR profile helped identify a subgroup of children with ADHD who had a psychopathological and functional profile consistent with the clinical concept of DESR, which is characterized by deficits in self-regulating the physiological arousal caused by strong emotions.
Abstract: Objective: Deficient emotional self-regulation (DESR) is characterized by deficits in self-regulating the physiological arousal caused by strong emotions. We examined whether a unique profile of the Child Behavior Checklist (CBCL) would help identify DESR in children with attention-deficit/hyperactivity disorder (ADHD). Methods: Subjects included 197 children with ADHD and 224 children without ADHD. We defined DESR if a child had an aggregate cut-off score of > 180 but 210) form has been previously associated with severe forms of mood and behavioral dysregulation in children with ADHD. All subjects were comprehensively assessed with structured diagnostic interviews and a wide range of functional measures. Results: Forty-four percent of children with ADHD had a positive CBCL-DESR...

103 citations


Journal ArticleDOI
TL;DR: A genome‐wide significant result is not found in a GWAS of German children with ADHD compared to controls and the second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.
Abstract: The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.

87 citations


Journal ArticleDOI
TL;DR: Despite a symptom-based standardized inclusion procedure according to DSM-IV criteria with defined symptom thresholds, centres may differ markedly in probands' ADHD symptom frequencies, particularly in genetic or neurobehavioral studies.
Abstract: The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with the combined type of attention deficit/hyperactivity disorder (ADHD-CT) and 1446 'unselected' siblings. The aim was to analyse the IMAGE sample with respect to demographic features (gender, age, family status, and recruiting centres) and psychopathological characteristics (diagnostic subtype, symptom frequencies, age at symptom detection, and comorbidities). A particular focus was on the effects of the study design and the diagnostic procedure on the homogeneity of the sample in terms of symptom-based behavioural data, and potential consequences for further analyses based on these data. Diagnosis was based on the Parental Account of Childhood Symptoms (PACS) interview and the DSM-IV items of the Conners' teacher questionnaire. Demographics of the full sample and the homogeneity of a subsample (all probands) were analysed by using robust statistical procedures which were adjusted for unequal sample sizes and skewed distributions. These procedures included multi-way analyses based on trimmed means and winsorised variances as well as bootstrapping. Age and proband/sibling ratios differed between participating centres. There was no significant difference in the distribution of gender between centres. There was a significant interaction between age and centre for number of inattentive, but not number of hyperactive symptoms. Higher ADHD symptom frequencies were reported by parents than teachers. The diagnostic symptoms differed from each other in their frequencies. The face-to-face interview was more sensitive than the questionnaire. The differentiation between ADHD-CT probands and unaffected siblings was mainly due to differences in hyperactive/impulsive symptoms. Despite a symptom-based standardized inclusion procedure according to DSM-IV criteria with defined symptom thresholds, centres may differ markedly in probands' ADHD symptom frequencies. Both the diagnostic procedure and the multi-centre design influence the behavioural characteristics of a sample and, thus, may bias statistical analyses, particularly in genetic or neurobehavioral studies.

Journal ArticleDOI
TL;DR: Findings are in line with studies of non-VCFS individuals at risk for schizophrenia and suggest that early decrements in temporal lobe gray matter may be predictive of increased risk of prodromal psychotic symptoms in youth with VCFS.

Journal ArticleDOI
TL;DR: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures, which suggests that lower IQ does not account for the key cognitive impairments observed in ADHD.
Abstract: BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ.MethodMultivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

Journal ArticleDOI
TL;DR: It is shown that the majority of BP-I disorder youth continue to experience persistent disorder into their mid and late adolescent years and its persistence is associated with high levels of morbidity and disability.

Journal ArticleDOI
TL;DR: A genome-wide association study of the Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales, in children with attention-deficit/hyperactivity disorder (ADHD) found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP.
Abstract: Objective A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behavior. We have conducted a genome-wide association study of the CBCL-DP in children with attention-deficit/hyperactivity disorder (ADHD). Method Families were ascertained at Massachusetts General Hospital and University of California, Los Angeles. Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. Genome-wide association analyses were conducted with the MQFAM multivariate extension of PLINK. Results CBCL data were available for 341 ADHD offspring from 339 ADHD affected trio families from the UCLA ( N = 128) and the MGH ( N = 213) sites. We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p TMEM132D , LRRC7 , SEMA3A , ALK , and STIP1 . Conclusions We found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP.

Journal ArticleDOI
TL;DR: This 5-year follow-up suggests that many girls with ADHD experience persistent symptoms and/or functional impairment through late adolescence and into early adulthood.
Abstract: Objective: The main aim of this study was to examine the age-dependent remission from ADHD in girls transitioning through childhood into adolescence and early adulthood. Method: We conducted a 5-year prospective follow-up study of 123 girls with ADHD and 106 non-ADHD control girls aged between 6 and 17 years at ascertainment. ADHD was considered persistent at follow-up if participants met full diagnostic criteria for DSM-IV ADHD or met residual criteria for DSM-IV ADHD with associated impairment (Global Age Forum [GAF] score < 60). Results: By age 16 years, ADHD was persistent in 71% (95% CI = 61-79%) of girls with ADHD. Participants with persistent ADHD at follow-up had more psychiatric comorbidity, behavior problems, and functional impairment than girls with ADHD in remission. Remitted ADHD, however, continued to be associated with functional impairment relative to non-ADHD controls. Persistence at 5 years was predicted by increased behavioral impairment at baseline. Conclusion: This 5-year follow-up suggests that many girls with ADHD experience persistent symptoms and/or functional impairment through late adolescence and into early adulthood. (J. of Att. Dis. 2010; XX(X) 1-XX)

Journal ArticleDOI
TL;DR: This randomized clinical trial showed that executive function deficits do not moderate the response to methylphenidate and measures ofexecutive function deficits are not associated with response to OROS-MPH.

Journal ArticleDOI
TL;DR: When ADHD probands are diagnosed by use of fixed symptom counts, the severity of the disorder in the proband sample may markedly differ between boys and girls and across age, particularly in samples with a large age range.
Abstract: The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with ADHD and 1446 unselected siblings. The aim was to describe and analyse questionnaire data and IQ measures from all probands and siblings. In particular, to investigate the influence of age, gender, family status (proband vs. sibling), informant, and centres on sample homogeneity in psychopathological measures. Conners' Questionnaires, Strengths and Difficulties Questionnaires, and Wechsler Intelligence Scores were used to describe the phenotype of the sample. Data were analysed by use of robust statistical multi-way procedures. Besides main effects of age, gender, informant, and centre, there were considerable interaction effects on questionnaire data. The larger differences between probands and siblings at home than at school may reflect contrast effects in the parents. Furthermore, there were marked gender by status effects on the ADHD symptom ratings with girls scoring one standard deviation higher than boys in the proband sample but lower than boys in the siblings sample. The multi-centre design is another important source of heterogeneity, particularly in the interaction with the family status. To a large extent the centres differed from each other with regard to differences between proband and sibling scores. When ADHD probands are diagnosed by use of fixed symptom counts, the severity of the disorder in the proband sample may markedly differ between boys and girls and across age, particularly in samples with a large age range. A multi-centre design carries the risk of considerable phenotypic differences between centres and, consequently, of additional heterogeneity of the sample even if standardized diagnostic procedures are used. These possible sources of variance should be counteracted in genetic analyses either by using age and gender adjusted diagnostic procedures and regional normative data or by adjusting for design artefacts by use of covariate statistics, by eliminating outliers, or by other methods suitable for reducing heterogeneity.

Journal ArticleDOI
TL;DR: The evidence that abnormalities of splicing may contribute to the liability toward neuropsychiatric disorders is reviewed, and a theoretical reworking of the concept of “gene‐focused” epidemiologic and neurobiologic investigations is provided.
Abstract: Alternative pre-mRNA splicing is a major mechanism by which the proteomic diversity of eukaryotic genomes is amplified. Much akin to neuropsychiatric disorders themselves, alternative splicing events can be influenced by genetic, developmental, and environmental factors. Here, we review the evidence that abnormalities of splicing may contribute to the liability toward these disorders. First, we introduce the phenomenon of alternative splicing and describe the processes involved in its regulation. We then review the evidence for specific splicing abnormalities in a wide range of neuropsychiatric disorders, including psychotic disorders (schizophrenia), affective disorders (bipolar disorder and major depressive disorder), suicide, substance abuse disorders (cocaine abuse and alcoholism), and neurodevelopmental disorders (autism). Next, we provide a theoretical reworking of the concept of "gene-focused" epidemiologic and neurobiologic investigations. Lastly, we suggest potentially fruitful lines for future research that should illuminate the nature, extent, causes, and consequences of alternative splicing abnormalities in neuropsychiatric disorders.

Journal ArticleDOI
TL;DR: This study is the first to examine CDH13 and neurocognitive functioning and may be viewed as exploratory, with the results presented providing interesting hypotheses for further testing.
Abstract: Different analytic strategies, including linkage, association and meta-analysis support a role of CDH13 in the susceptibility to attention deficit/hyperactivity disorder (ADHD). CDH13 codes for cadherin 13 (or H-cadherin), which is a member of a family of calcium-dependent cell-cell adhesion proteins and a regulator of neural cell growth. We tested the association between CDH13 on three executive functioning tasks that are promising endophenotypes of ADHD. An adjusted linear regression analysis was performed in 190 ADHD-affected Dutch probands of the IMAGE project. Three executive functions were examined: inhibition, verbal and visuo-spatial working memory (WM). We tested 2632 single nucleotide polymorphisms (SNPs) within CDH13 and 20 kb up- and downstream of the gene (capturing regulatory sequences). To adjust for multiple testing within the gene, we applied stringent permutation steps. Intronic SNP rs11150556 is associated with performance on the Verbal WM task. No other SNP showed gene-wide significance with any of the analyzed traits, but a 72-kb SNP block located 446 kb upstream of SNP rs111500556 showed suggestive evidence for association (P-value range 1.20E-03 to 1.73E-04) with performance in the same Verbal WM task. This study is the first to examine CDH13 and neurocognitive functioning. The mechanisms underlying the associations between CDH13 and the clinical phenotype of ADHD and verbal WM are still unknown. As such, our study may be viewed as exploratory, with the results presented providing interesting hypotheses for further testing.

Journal ArticleDOI
TL;DR: It is shown that DMN suppression is likely linked to DAT1 and to severity of inattention in ADHD, and may be a target of DAT2 effects, and lie on the path between the gene and inatt attention in ADHD.
Abstract: Alterations in working memory, default-mode network (DMN), and dopamine transporter have all been proposed as endophenotypes for attention-deficit/hyperactivity disorder (ADHD). Despite evidence that these systems are interrelated, their relationship to each other has never been studied in the context of ADHD. In order to understand the potential mediating effects of task-positive and task-negative networks between DAT1 and diagnosis, we tested effects of genotype and diagnosis on regions of positive and negative BOLD signal change (as measured with fMRI) in 53 adults with ADHD and 38 control subjects during a working memory task. We also examined the relationship of these responses to ADHD symptoms. Our results yielded four principal findings: 1) association of the DAT1 9R allele with adult ADHD, 2) marginal DAT1 association with task-related suppression in left medial PFC, 3) marginal genotype×diagnosis interaction in the dorsal anterior cingulate cortex, and 4) correlation of DMN suppression to ADHD symptoms. These findings replicate the association of the 9R allele with adult ADHD. Further, we show that DMN suppression is likely linked to DAT1 and to severity of inattention in ADHD. DMN may therefore be a target of DAT1 effects, and lie on the path between the gene and inattention in ADHD.

Journal ArticleDOI
TL;DR: The results support the genetic distinctiveness of IDIR and delay aversion in ADHD and implicate serotonin function in delay aversion.

Journal ArticleDOI
TL;DR: Questions are raised about the homogeneity of VDM as an endophenotype, about methodological issues related to sampling, and about psychometric issues that impact the utility of the CVLT for detecting VDM deficits in nonpsychotic relatives of persons with schizophrenia.

Journal ArticleDOI
TL;DR: Some evidence is provided that MAOA may be associated with the ADHD‐HI subtype and support the association between MAOA and impulsivity, which may be a potential endophenotype of ADHD.
Abstract: Monoamine oxidase A (MAOA) plays a critical role in the metabolism of monoamine neurotransmitters including serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Genetic studies have found an association between MAOA and attentiondeficit/hyperactivity disorder (ADHD), especially impulsivity. However, there has been inconsistency among studies which may be due to the complexity and heterogeneity of ADHD, including its sexual dimorphism and the presence of several subtypes. We conducted transmission disequilibrium tests (TDTs) in 1,253 trios and found no association between five single nucleotide polymorphisms (SNPs) of MAOA with ADHD in general or in the predominantly inattentive (ADHD-I) or combined types (ADHD-C), but with the predominantly hyperactive/impulsivity type (ADHD-HI). The association with MAOA was restricted to males, especially males with ADHD-HI. Logistic regression analyses of data from 1,824 cases and 957 controls did not indicate any association. We used analysis of covariance to analyze the association between MAOA genotype with the ‘‘inhibit’’ factor of the Behavior Rating Inventory of Executive Function (BRIEF) in 640 probands and performance on the Stroop test in 810 probands. Probands homozygous for risk alleles found in the TDT test had higher ‘‘inhibit’’ scores on the BRIEF scale which represents more severe impulsivity; this results also was restricted to males. No association was found with Stroop test performance. In conclusion, our results provide some evidence that MAOA may be associated with the ADHD-HI subtype and support the association between MAOA and impulsivity, which may be a potential endophenotype of ADHD. However, the results were strongly influenced by gender. � 2011 Wiley-Liss, Inc.


Journal ArticleDOI
TL;DR: The data suggest a novel mechanism whereby SLC9A9 sequence variants and abnormalities in gene expression could contribute to the ADHD‐like symptoms of rat models and possibly the pathophysiology of ADHD in humans.
Abstract: SLC9A9 (solute carrier family 9, member 9, also known as Na+/H+ exchanger member (NHE9)) is a membrane protein that regulates the luminal pH of the recycling endosome, an essential organelle for synaptic transmission and plasticity. SLC9A9 has been implicated in human attention deficit hyperactivity disorder (ADHD) and in rat studies of hyperactivity. We examined the SLC9A9 gene sequence and expression profile in prefrontal cortex, dorsal striatum and hippocampus in two genetic rat models of ADHD. We report two mutations in a rat model of inattentive ADHD, the WKY/NCrl rat, which affect the interaction of SLC9A9 with calcineurin homologous protein (CHP). We observed an age-dependent abnormal expression of SLC9A9 in brains of this inattentive model and in the Spontaneous Hypertensive Rat (SHR) model of ADHD. Our data suggest a novel mechanism whereby SLC9A9 sequence variants and abnormalities in gene expression could contribute to the ADHD-like symptoms of rat models and possibly the pathophysiology of ADHD in humans.

Journal ArticleDOI
TL;DR: For instance, this paper found that youth with bipolar I disorder are at high risk for significant impairments in academic functioning, such as a decrease in reading and arithmetic ability and a higher risk for speech/language disorder.
Abstract: Although psychometrically-defined executive function deficits (EFDs) and ecologically valid functional outcomes have been documented among youth with bipolar I (BP-I) disorder, little is known about their association. We hypothesized that EFDs would be associated with significant ecologically valid impairments beyond those predicted by having BP-I disorder. Youth with BP-I disorder were ascertained from psychiatric clinics and community sources. We defined EFDs as having at least two out of eight EF measures impaired from a battery of six tests. Significantly more youth with BP-I disorder had EFDs than controls (45% versus 17%). Comparisons were made between controls without EFDs ( N =81), controls with EFDs ( N =17), BP-I youth without EFDs ( N =76), and BP-I youth with EFDs ( N =62). EFDs were associated with an increased risk for placement in a special class and a decrease in academic achievement (WRAT-3 reading and arithmetic). EFDs in BP-I subjects were associated with an increased risk for speech/language disorder (as assessed in the K-SADS-E) relative to BP-I subjects without EFDs. Youth with BP-I disorder and EFDs are at high risk for significant impairments in academic functioning.

Journal ArticleDOI
TL;DR: A functional MRI study of working memory in adolescents and young adults at genetic risk for bipolar disorder: preliminary findings.
Abstract: Thermenos HW, Makris N, Whitfield-Gabrieli S, Brown AB, Giuliano AJ, Lee EH, Faraone SV, Tsuang MT, Seidman LJ. A functional MRI study of working memory in adolescents and young adults at genetic risk for bipolar disorder: preliminary findings. Bipolar Disord 2011: 13: 272–286. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: In this report, we seek to (i) identify a potential neuroimaging endophenotype for bipolar disorder (BD) in emotion regulatory and autonomic circuitry in young first-degree relatives of persons with BD; and (ii) replicate our previous work identifying the functional neuroanatomy of working memory (WM) in an older sample of relatives of persons with BD. Methods: Ten adolescent and young adult (age 13–24) unmedicated, non-ill, first-degree relatives of persons with BD (RELS) and 10 demographically comparable healthy controls performed a 2-back WM task and a 0-back control task during functional magnetic resonance imaging (fMRI). fMRI data were collected on a 1.5 Tesla scanner and analyzed using SPM-2. Mood was assessed on the day of scanning. Results: The groups did not differ on any demographic, neuropsychological, or in-scanner task performance variables. In contrast to controls, RELS showed (i) weak task-dependent modulation activity in the cerebellar vermis (CV), insula, and amygdala/parahippocampal region, and (ii) exaggerated modulation of activity in the frontopolar cortex and brainstem, even after controlling for potential confounders. Many of the group differences were driven by differences in activity in the low-level (0-back) baseline task. Conclusions: Young, unmedicated RELS exhibited altered task-dependent modulation of frontopolar, CV, and insula activity during WM, especially during the low-level (0-back) baseline task. Results are largely consistent with our initial study of older adult RELS, suggesting these alterations may represent biomarkers of genetic risk for BD.

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TL;DR: It is suggested that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.
Abstract: Objective We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD). Method Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD. Results We observed no genome-wide statistically significant findings, but a SNP in a K+-dependent Na+/Ca2+ exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p Conclusions The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.

Journal ArticleDOI
TL;DR: In this article, the authors used the publicly available data of 947 families participating in the International Multi-Centre ADHD Genetics (IMAGE) study to conduct an in silico fine mapping study of previously associated genomic locations, and to attempt replication of previously reported candidate genes for intelligence.
Abstract: Intelligence is a highly heritable trait for which it has proven difficult to identify the actual genes. In the past decade, five whole-genome linkage scans have suggested genomic regions important to human intelligence; however, so far none of the responsible genes or variants in those regions have been identified. Apart from these regions, a handful of candidate genes have been identified, although most of these are in need of replication. The recent growth in publicly available data sets that contain both whole genome association data and a wealth of phenotypic data, serves as an excellent resource for fine mapping and candidate gene replication. We used the publicly available data of 947 families participating in the International Multi-Centre ADHD Genetics (IMAGE) study to conduct an in silico fine mapping study of previously associated genomic locations, and to attempt replication of previously reported candidate genes for intelligence. Although this sample was ascertained for attention deficit/hyperactivity disorder (ADHD), intelligence quotient (IQ) scores were distributed normally. We tested 667 single nucleotide polymorphisms (SNPs) within 15 previously reported candidate genes for intelligence and 29451 SNPs in five genomic loci previously identified through whole genome linkage and association analyses. Significant SNPs were tested in four independent samples (4,357 subjects), one ascertained for ADHD, and three population-based samples. Associations between intelligence and SNPs in the ATXN1 and TRIM31 genes and in three genomic locations showed replicated association, but only in the samples ascertained for ADHD, suggesting that these genetic variants become particularly relevant to IQ on the background of a psychiatric disorder.