Recent Submissions

  • Absence of Gender Effects on Attention Deficit Hyperactivity Disorder: Findings in Nonreferred Subjects

    Biederman, Joseph; Kwon, Anne; Aleardi, Megan; Chouinard, Virginie-Anne; Marino, Teresa; Cole, Heather; Mick, Eric; Faraone, Stephen V. (American Psychiatric Association Publishing, 2005-06)
    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. Ninetyeight 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 nonreferred males and females with ADHD did not differ in DSM-IV subtypes of ADHD, psychiatric comorbidity, or treatment history. They also showed similar levels of cognitive, psychosocial, school, and family functioning. Conclusions: These 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.
  • Neuropsychological intra-individual variability explains unique genetic variance of ADHD and shows suggestive linkage to chromosomes 12, 13, and 17

    Frazier-Wood, Alexis C.; Bralten, Janita; Arias-Vasquez, Alejandro; Luman, Marjolein; Ooterlaan, Jaap; Sergeant, Joseph; Faraone, Stephen V.; Buitelaar, Jan; Franke, Barbara; Kuntsi, Jonna; et al. (Wiley, 2012-01-05)
    Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder that is usually accompanied by neuropsychological impairments. The use of heritable, psychometrically robust traits that show association with the disorder of interest can increase the power of gene-finding studies. Due to the robust association of intra-individual variability with ADHD on a phenotypic and genetic level, intra-individual variability is a prime candidate for such an attempt. We aimed to combine intra-individual variability measures across tasks into one more heritable measure, to examine the relatedness to other cognitive factors, and to explore the genetic underpinnings through quantitative trait linkage analysis. Intra-individual variability measures from seven tasks were available for 238 ADHD families (350 ADHD-affected and 195 non-affected children) and 147 control families (271 children). Intra-individual variability measures from seven different tasks shared common variance and could be used to construct an aggregated measure. This aggregated measure was largely independent from other cognitive factors related to ADHD and showed suggestive linkage to chromosomes 12q24.3 (LOD ¼ 2.93), 13q22.2 (LOD ¼ 2.36), and 17p13.3 (LOD ¼ 2.00). A common intra-individual variability construct can be extracted from very diverse neuropsychological tasks; this construct taps into unique genetic aspects of ADHD and may relate to loci conferring risk for ADHD (12q24.3 and 17p13.3) and possibly autism (12q24.3). Given that joining of data across sites boosts the power for genetic analyses, our findings are promising in showing that intra-individual variability measures are viable candidates for across site analyses where different tasks have been used.
  • Laboratory-Observed Behavioral Disinhibition in the Young Offspring of Parents With Bipolar Disorder: A High-Risk Pilot Study

    Hirshfeld-Becker, Dina R.; Biederman, Joseph; Henin, Aude; Faraone, Stephen V.; Cayton, Gabrielle A.; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2006-02)
    Objective: This study tested whether behavioral disinhibition is more prevalent among offspring of parents with bipolar disorder than among offspring of parents without bipolar disorder. Method: The authors conducted a secondary analysis of data from a preexisting high-risk study of offspring at risk for panic disorder and depression (N=278) that had included some children with parents who had bipolar disorder (N=34). Children (ages 2–6) had been classified as behaviorally inhibited, disinhibited, or neither in laboratory assessments. Results: Offspring of bipolar parents had significantly higher rates of behavioral disinhibition than offspring of parents without bipolar disorder. Behavioral inhibition did not differ between groups. Differences were not accounted for by parental panic disorder or major depression or by parental history of attention deficit hyperactivity disorder, conduct disorder, antisocial personality, or substance use disorders. Conclusions: Results suggest a familial link between bipolar disorder in parents and behavioral disinhibition in their offspring. Behavioral disinhibition may be a familially transmitted predisposing factor for dysregulatory distress later in life.
  • Impact of Psychometrically Defined Deficits of Executive Functioning in Adults With Attention Deficit Hyperactivity Disorder

    Biederman, Joseph; Petty, Carter; Fried, Ronna; Fontanella, Jessie; Doyle, Alysa E.; Seidman, Larry J.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2006-10)
    Objective: The association between deficits in executive functioning and functional outcomes was examined among adults with attention deficit hyperactivity disorder (ADHD). Method: Subjects were adults who did (N=213) and did not (N=145) meet DSMIV criteria for ADHD. The authors defined having deficits in executive functioning as having at least two measures of executive functioning with scores 1.5 standard deviations below those of matched comparison subjects. Results: Significantly more adults with ADHD had deficits of executive functioning than comparison subjects. Deficits of executive functioning were associated with lower academic achievement, irrespective of ADHD status. Subjects with ADHD with deficits of executive functioning had a significantly lower socioeconomic status and a significant functional morbidity beyond the diagnosis of ADHD alone. Conclusions: Psychometrically defined deficits of executive functioning may help identify a subgroup of adults with ADHD at high risk for occupational and academic underachievement. More efforts are needed to identify cost-effective approaches to screen individuals with ADHD for deficits of executive functioning.
  • Familial Risk Analyses of Attention Deficit Hyperactivity Disorder and Substance Use Disorders

    Biederman, Joseph; Petty, Carter R.; Wilens, Timothy E.; Fraire, Maria G.; Purcell, Caitlin A.; Mick, Eric; Monuteaux, Michael C.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2008-01)
    Objective: A robust and bidirectional comorbidity between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorder (alcohol or drug abuse or dependence) has been consistently reported in the extant literature. Method: First-degree relatives from a large group of pediatrically and psychiatrically referred boys with (112 probands, 385 relatives) and without (105 probands, 358 relatives) ADHD were comprehensively assessed by blind raters with structured diagnostic interviews. Familial risk analysis examined the risks in first-degree relatives for ADHD, psychoactive substance use disorder, alcohol dependence, and drug dependence after stratifying probands by the presence and absence of these disorders. Results: ADHD in the proband was consistently associated with a significant risk for ADHD in relatives. Drug dependence in probands increased the risk for drug dependence in relatives irrespective of ADHD status, whereas alcohol dependence in relatives was predicted only by ADHD probands with comorbid alcohol dependence. In addition, ADHD in the proband predicted drug dependence in relatives, and drug dependence in comparison probands increased the risk for ADHD in relatives. Both alcohol dependence and drug dependence bred true in families without evidence for a common risk between these disorders. Conclusions: Patterns of familial risk analysis suggest that the association between ADHD and drug dependence is most consistent with the hypothesis of variable expressivity of a common risk between these disorders, whereas the association between ADHD and alcohol dependence is most consistent with the hypothesis of independent transmission of these disorders. Findings also suggest specificity for the transmission of alcohol and drug dependence.
  • Adult Psychiatric Outcomes of Girls With Attention Deficit Hyperactivity Disorder: 11-Year Follow-Up in a Longitudinal Case-Control Study

    Biederman, Joseph; Petty, Carter R.; Monuteaux, Michael C.; Fried, Ronna; Byrne, Deirdre; Mirto, Tara; Spencer, Thomas; Wilens, Timothy E.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2010-04)
    Objective: Few follow-up studies have been conducted of girls with ADHD, and none have followed girls into adulthood. The authors sought to estimate the prevalence of psychopathology in girls with and without ADHD followed into young adulthood. Method: The authors conducted a longitudinal case-control study of 6- to 18-year-old girls with (N=140) and without (N=122) ADHD ascertained from psychiatric and pediatric sources. At the 11-year follow-up, 96 (69%) of the girls with ADHD and 91 (75%) of the comparison girls were reassessed (mean age=22 years). Participants were blindly assessed by structured diagnostic interviews. Results: Lifetime and 1-year risks for all composite categories of psychopathology were significantly greater in girls with ADHD grown up relative to comparison girls; lifetime hazard ratios were 7.2 (95% CI=4.0–12.7) for antisocial disorders, 6.8 (95% CI=3.7–12.6) for mood disorders, 2.1 (95% CI=1.6–2.9) for anxiety disorders, 3.2 (95% CI=2.0–5.3) for developmental disorders, 2.7 (95% CI=1.6–4.3) for addictive disorders, and 3.5 (95% CI=1.6–7.3) for eating disorders. For lifetime psychopathology, all six composite categories remained statistically significant after controlling for other baseline psychopathology. Except for addictive disorders, significant 1-year findings remained significant after controlling for baseline psychopathology. The 1-year prevalences of composite disorders were not associated with lifetime or 1-year use of ADHD medication. Conclusions: By young adulthood, girls with ADHD were at high risk for antisocial, addictive, mood, anxiety, and eating disorders. These prospective findings, previously documented in boys with ADHD, provide further evidence for the high morbidity associated with ADHD across the life cycle.
  • Deficient Emotional Self-Regulation and Adult Attention Deficit Hyperactivity Disorder: A Family Risk Analysis

    Surman, Craig B.H.; Biederman, Joseph; Spencer, Thomas; Yorks, Dayna; Miller, Carolyn A.; Petty, Carter R.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2011-06)
    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 in siblings of the ADHD proband groups. Conclusions: The pattern of inheritance of ADHD with DESR preliminarily suggests that DESR may be a familial subtype of ADHD. Our data suggest that DESR is not an expression of other axis I DSM-IV disorders or of nonfamilial environmental factors. The authors cannot exclude contribution of non-axis-I DSM-IV disorders to risk for DESR and cannot determine whether the cosegregation of ADHD in DESR within families is a result of genes or familial environmental risk factors. Further investigation of DESR and its correlates and treatment both in and outside the context of ADHD is warranted.
  • Examining the Comorbidity Between Attention Deficit Hyperactivity Disorder and Bipolar I Disorder: A Meta-Analysis of Family Genetic Studies

    Faraone, Stephen V.; Biederman, Joseph; Wozniak, Janet (American Psychiatric Association Publishing, 2012-12)
    Objective: The existence of comorbidity between attention deficit hyperactivity disorder (ADHD) and bipolar I disorder has been documented in clinical and epidemiological studies, in studies of children and adults, and in diagnosed ADHD and bipolar I patient samples. Yet questions remain about the validity of diagnosing bipolar I disorder in ADHD youth. The authors aim to clarify these issues by reviewing family genetic studies of ADHD and bipolar I disorder. Method: The authors applied randomeffects meta-analysis to family genetic studies of ADHD and bipolar I disorder. Twenty bipolar proband studies provided 37 estimates of the prevalence of ADHD in 4,301 relatives of bipolar probands and 1,937 relatives of comparison probands. Seven ADHD proband studies provided 12 estimates of the prevalence of bipolar I disorder in 1,877 relatives of ADHD probands and 1,601 relatives of comparison probands. Results: These studies found a significantly higher prevalence of ADHD among relatives of bipolar probands and a significantly higher prevalence of bipolar I disorder among relatives of ADHD probands. These results could not be accounted for by publication biases, unusual results from any one observation, sample characteristics, or study design features. The authors found no evidence of heterogeneity in the ADHD or bipolar family studies. Conclusions: The results suggest that ADHD plus bipolar comorbidity cannot be accounted for by misdiagnoses, but additional research is needed to rule out artifactual sources of comorbidity. More research is also needed to determine whether comorbidity of ADHD and bipolar I disorder constitutes a familial subtype distinct from its constituent disorders, which if confirmed would have implications for diagnostic nosology and genetic studies.
  • Effectiveness and Tolerability of Tomoxetine in Adults With Attention Deficit Hyperactivity Disorder

    Spencer, Thomas; Biederman, Joseph; Wilens, Timothy; Prince, Jeffry; Hatch, Mary; Jones, Janice; Harding, Margaret; Faraone, Stephen V.; Seidman, Larry (American Psychiatric Association Publishing, 1998-05)
    Objective: The authors assessed the experimental noradrenergic compound tomoxetine as an alternative treatment for adult attention deficit hyperactivity disorder (ADHD). Method: They conducted a double-blind, placebo-controlled, crossover study of tomoxetine in 22 adults with well-characterized ADHD. Results: Treatment with tomoxetine at an average oral dose of 76 mg/day was well tolerated. Drug-specific improvement in ADHD symptoms was highly significant overall and sufficiently robust to be detectable in a parallel-groups comparison restricted to the first 3 weeks of the protocol. Eleven of 21 patients showed improvement after receiving tomoxetine, compared with only two of 21 patients who improved after receiving placebo. Significant tomoxetine-associated improvement was noted on neuropsychological measures of inhibitory capacity from Stroop tests. Conclusions: This preliminary study showed that tomoxetine was effective in treating adult ADHD and was well tolerated. These promising results provide support for further studies of tomoxetine over an extended period of treatment.
  • Brain Correlates of the Interaction Between5-HTTLPRand Psychosocial Stress Mediating Attention Deficit Hyperactivity Disorder Severity

    van der Meer, Dennis; Hoekstra, Pieter J.; Zwiers, Marcel; Mennes, Maarten; Schweren, Lizanne J.; Franke, Barbara; Heslenfeld, Dirk J.; Oosterlaan, Jaap; Faraone, Stephen V.; Buitelaar, Jan K.; et al. (American Psychiatric Association Publishing, 2015-08)
    Objective: The serotonin transporter 5-HTTLPR genotype has been found to moderate the effect of stress on severity of attention deficit hyperactivity disorder (ADHD), with stronger effects of stress in carriers of the short allele than in individuals homozygous for the long allele. The underlying neurobiological mechanism of this gene-environment interaction in ADHD is unknown. The authors aimed to determine whether 5-HTTLPR moderates the effect of stress on brain gray matter volume and, if so, which brain regions mediate the effect of this gene-environment interaction on ADHD severity. Method: Structural MRI, 5-HTTLPR genotype, and stress exposure questionnaire data were available for 701 adolescents and young adults participating in the multicenter ADHD cohort NeuroIMAGE study (from 385 families; 291 with ADHD, 78 with subthreshold ADHD, 332 healthy comparison subjects; 55.8% male; average age: 17.0 years). ADHD symptom count was determined through multi-informant questionnaires. For the analysis, a whole-brain voxel-based morphometry approach was combined with mediation analysis. Results: Stress exposure was associated with significantly less gray matter volume in the precentral gyrus, middle and superior frontal gyri, frontal pole, and cingulate gyrus in S-allele carriers compared with participants homozygous for the L-allele. The association of this gene-environment interaction with ADHD symptom count was mediated by gray matter volume in the frontal pole and anterior cingulate gyrus. Conclusions: 5-HTTLPR genotype moderates the effect of stress on brain regions involved in social cognitive processing and cognitive control. Specifically, regions important for cognitive control link this gene-environment interaction to ADHD severity.
  • Family based association study of pediatric bipolar disorder and the dopamine transporter gene (SLC6A3)

    Mick, Eric; Kim, Jang Woo; Biederman, Joseph; Wozniak, Janet; Wilens, Timothy; Spencer, Thomas; Smoller, Jordan W.; Faraone, Stephen V. (Wiley, 2008-10-05)
    Thedopaminetransportergene(SLC6A3) isacompelling candidate for pediatric bipolar disorder because (a) it has been associated with ADHD, (b) bipolar comorbidity with ADHD has been hypothesized to be an etiologically distinct familial subtype (c) blockade of the dopamine transporter with psychostimulants can induce mania in susceptible individualsand(d) previous studies have implicated the gene in bipolar disorder in adults. We conducted a family-based association study of SLC6A3 in 170 affected offspring trios defined by a child (12.9 5.3 years of age)with DSM-IV Bipolar-I disorder. Twenty-eight tag SNPs were chosen from the CEU (European) population of the International HapMap project (www.hapmap.org). Results indicated nominally positive association for 4 SNPs (rs40184, rs11133767, rs3776512, and rs464049), but only rs40184 survived correction formultiple statistical comparisons (P¼0.038). This is the first examination of the association with SLC6A3 and bipolar disorder in children and, like previous findings in adults with bipolar disorder, we found evidence of association with SNPs in the 30 region of the gene. These data provide suggestive evidence supporting a role for SLC6A3 in the etiology of pediatric bipolar disorder.
  • Pediatric mania: a developmental subtype of bipolar disorder?

    Biederman, Joseph; Mick, Eric; Faraone, Stephen V; Spencer, Thomas; Wilens, Timothy E; Wozniak, Janet (Elsevier BV, 2000-09)
    Despite ongoing controversy, the view that pediatric mania is rare or nonexistent has been increasingly challenged not only by case reports, but also by systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include: 1) its pattern of comorbidity may be unique by adult standards, especially its overlap with attention-deficit/hyperactivity disorder, aggression, and conduct disorder; 2) its overlap with substance use disorders; 3) its association with trauma and adversity; and 4) its response to treatment is atypical by adult standards. Biol Psychiatry 2000;48: 458–466 © 2000 Society of Biological Psychiatry.
  • ADHD and DAT1: Further evidence of paternal over-transmission of risk alleles and haplotype

    Hawi, Z.; Kent, L.; Hill, M.; Anney, R.J.L.; Brookes, K.J.; Barry, E.; Franke, B.; Banaschewski, T.; Buitelaar, J.; Ebstein, R.; et al. (Wiley, 2009)
    We [Hawi et al. (2005); Am J Hum Genet 77:958–965] reported paternal over-transmission of risk alleles in some ADHD-associated genes. This was particularly clear in the case of the DAT1 3′-UTR VNTR. In the current investigation, we analyzed three new samples comprising of 1,248 ADHD nuclear families to examine the allelic over-transmission of DAT1 in ADHD. The IMAGE sample, the largest of the three-replication samples, provides strong support for a parent of origin effect for allele 6 and the 10 repeat allele (intron 8 and 3′-UTR VNTR, respectively) of DAT1. In addition, a similar pattern of over-transmission of paternal risk haplotypes (constructed from the above alleles) was also observed. Some support is also derived from the two smaller samples although neither is independently significant. Although the mechanism driving the paternal overtransmission of the DAT risk alleles is not known, these finding provide further support for this phenomenon.
  • Transcriptome-wide gene expression in a rat model of attention deficit hyperactivity disorder symptoms: Rats developmentally exposed to polychlorinated biphenyls

    Sazonova, Nadezhda A.; DasBanerjee, Tania; Middleton, Frank A.; Gowtham, Sriharsha; Schuckers, Stephanie; Faraone, Stephen V. (Wiley, 2011-09-14)
    Polychlorinated biphenyls (PCB) exposure in rodents provides a useful model for the symptoms of Attention deficit hyperactivity disorder (ADHD). The goal of this study is to identify genes whose expression levels are altered in response to PCB exposure. The brains from 48 rats separated into two age groups of 24 animals each (4 males and 4 females for each PCB exposure level (control, PCB utero, and PCB lactational)) were harvested at postnatal days 23 and 35, respectively. The RNA was isolated from three brain regions of interest and was analyzed for differences in expression of a set of 27,342 transcripts. Two hundred seventy-nine transcripts showed significant differential expression due to PCB exposure mostly due to the difference between PCB lactational and control groups. The cluster analysis applied to these transcripts revealed that significant changes in gene expression levels in PFC area due to PCB lactational exposure. Our pathway analyses implicated 27 significant canonical pathways and 38 significant functional pathways. Our transcriptomewide analysis of the effects of PCB exposure shows that the expression of many genes is dysregulated by lactational PCB exposure, but not gestational exposure and has highlighted biological pathways that might mediate the effects of PCB exposure on ADHD-like behaviors seen in exposed animals. Our work should further motivate studies of fatty acids in ADHD, and further suggests that another potentially druggable pathway, oxidative stress,may play a role in PCB inducedADHD behaviors
  • The monoamine oxidase B gene exhibits significant association to ADHD

    Li, Jun; Wang, Yufeng; Hu, Songnian; Zhou, Rulun; Yu, Xiaomin; Wang, Bing; Guan, Lili; Yang, Li; Zhang, Feng; Faraone, Stephen V. (Wiley, 2008)
    Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition with strong genetic basis. Recent work in China indicated that ADHD may be linked to Xp1–2 in the Han Chinese population. The gene encoding monoamine oxidase B (MAOB), the main enzyme degrading dopamine in the human brain, is located in this region. The current study sequenced the exons and the 50 and 30 flanking regions of theMAOBgene and found four common variants including 2276C>T and 2327C>T in exon 15, rs1799836 in intron 13 and rs1040399 in 30-UTR. We assessed the association of these variants with ADHD in 548 trios collected from 468 males and 80 females probands. TDT analysis showed that alleles of each polymorphism were preferentially transmitted to probands (rs1799836, P¼3.28E-15; rs1040399, P¼1.87E-6; 2276T>C or 2327T>C, P¼2.20E-6) and haplotype-based TDT analyses also found distorted transmission. In conclusion, this study provides the strongest evidence for the involvement of MAOB gene in the etiology of ADHD to date, at least in Han Chinese population.
  • The multidimensionality of schizotypy in nonpsychotic relatives of patients with schizophrenia and its applications in ordered subsets linkage analysis of schizophrenia

    Lien, Yin-Ju; Tsuang, Hui-Chun; Chiang, Abigail; Liu, Chih-Min; Hsieh, Ming H.; Hwang, Tzung-Jeng; Liu, Shi K.; Hsiao, Po-Chang; Faraone, Stephen V.; Tsuang, Ming T.; et al. (Wiley, 2009)
    This study aimed to examine the multidimensionality of schizotypy and validate the structure using ordered subset linkage analyses on information from both relatives’ schizotypy and probands’ schizophrenia symptoms. A total of 203 and 1,310 nonpsychotic first-degree relatives from simplex and multiplex schizophrenia families, respectively, were interviewed with the Diagnostic Interview for Genetic Studies, which contains a modified Structured Interview for Schizotypy. Using Mplus program with categorical factor indicators, a four-factor model (Negative Schizotypy, Positive Schizotypy, Interpersonal Sensitivity, and Social Isolation/Introversion) was extracted by exploratory factor analysis from relatives of simplex families and was confirmed in relatives of multiplex families. The validity of each factor was supported by distinct linkage findings resulting from ordered subset analysis based on different combinations of schizophrenia–schizotypy factors. Six chromosomal regions with significant increase in nonparametric linkage z score (NPL-Z) were found as follows: 15q21.1 (NPLZ ¼3.60) for Negative Schizophrenia–Negative Schizotypy, 10q22.3 (NPL-Z¼3.83) and 15q21.3 (NPL-Z¼3.36) for Negative Schizophrenia–Social Isolation/Introversion, 5q14.2 (NPL-Z¼3.20) and 11q23.3 (NPL-Z¼3.31) for Positive Schizophrenia–Positive Schizotypy, and 4q32.1 (NPL-Z¼3.31- ) for Positive Schizophrenia–Interpersonal Sensitivity. The greatest NPL-Z of 3.83 on 10q22.3 in the subset was significantly higher than the greatest one of 2.88 in the whole sample (empirical P-value¼0.04). We concluded that a consistent four-factor model of schizotypy could be derived in nonpsychotic relatives across families of patients with different genetic loadings in schizophrenia. Their differential relations to linkage signals have etiological implications and provide further evidence for their validity. 2009 Wiley-Liss, Inc.
  • Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder

    Mick, Eric; Neale, Benjamin; Middleton, Frank A.; McGough, James J.; Faraone, Stephen V. (Wiley, 2008-12-05)
    We conducted a genome-wide association study of symptom response in an open-label study of a methylphenidate transdermal system (MTS). All DNA extraction and genotyping was conducted at SUNY Upstate Medical University using the Affymetrix Genome-Wide Human SNP Array 6.0. All quality control and association analyses were conducted using the software package PLINK. After data cleaning and quality control, there were 187 subjects (72% (N¼135) male) with mean age 9.2 2.0 years and 319,722 SNPs available for analysis. The most statistically significant association (rs9627183 andrs11134178;P¼3 10 6) fell short of the threshold for a genome-wide significant association. The most intriguing association amongsuggestivefindings(rs3792452;P¼2.6 10 5) was with the metabotropic glutamate receptor 7 gene (GRM7) as it is expressed in brain structures also previously associated with ADHD. Among the 102 available SNPs covering previously studied candidate genes, two SNPs within the norepinephrine transporter gene (NET, SLC6A2) were significant at P 1 10 2. These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate.
  • Report from the second international meeting of the attention deficit hyperactivity disorder Molecular Genetics Network

    Faraone, Stephen V. (Wiley, 2001)
    Given evidence from twin, family, and adoption studies of genetic influence on attention deficit hyperactivity disorder (ADHD), a growing number of researchers have initiated molecular genetics studies to explore the influence of specific genes on this condition. In 1999, these investigators convened to discuss ways of sharing information and facilitating collaborations across research sites. Enthusiastic response to this first conference prompted an even larger group of investigators to come together this year. This recent meeting, held in London, began with a presentation of Hypescheme, an operational criteria checklist developed in an effort to promote the reliable communication of diagnostic and other relevant clinical information related to ADHD. The benefits and limitations of Hypescheme, as well as the continued challenges to collaboration, were discussed. A new ADHD-specific rating scale, developed to be of use in genetic analyses, was also presented. Focus then turned to collaborative projects proposed by investigators and practical suggestions regarding joint data analyses projects. Finally, new data from individual sites were presented. Because the mode of inheritance of ADHD is likely to be complex, efforts to collaborate and cross-validate findings remain an important priority for researchers studying the molecular genetics of this disorder. © 2001 Wiley-Liss, Inc.
  • The dopamine receptor D4 7-repeat allele influences neurocognitive functioning, but this effect is moderated by age and ADHD status: An exploratory study

    Altink, Marieke E.; Rommelse, Nanda N.J.; Slaats-Willemse, Dorine I.E.; Väsquez, Alejandro Arias; Franke, Barbara; Buschgens, Cathelijne J.M.; Fliers, Ellen A.; Faraone, Stephen V.; Sergeant, Joseph A.; Oosterlaan, Jaap; et al. (Informa UK Limited, 2011-11-23)
    Objectives. Evidence suggests the involvement of the dopamine D4 receptor gene ( DRD4 ) in the pathogenesis of ADHD, but the exact mechanism is not well understood. Earlier reports on the effects of DRD4 polymorphisms on neurocognitive and neuroimaging measures are inconsistent. This study investigated the functional consequences of the 7-repeat allele of DRD4 on neurocognitive endophenotypes of ADHD in the Dutch subsample of the International Multicenter ADHD Genetics study. Methods. Participants were 350 children (5 – 11.5 years) and adolescents (11.6 – 19 years) with ADHD and their 195 non-affected siblings. An overall measure of neuropsychological functioning was derived by principal component analysis from five neurocognitive and five motor tasks. The effects of DRD4 and age were examined using Linear Mixed Model analyses. Results. The analyses were stratified for affected and non-affected participants after finding a significant three-way interaction between ADHD status, age and the 7-repeat allele. Apart from a main effect of age, a significant interaction effect of age and DRD4 was found in non-affected but not in affected participants, with non-affected adolescent carriers of the 7-repeat allele showing worse neuropsychological performance. In addition, carrying the 7-repeat allele of DRD4 was related to a significantly worse performance on verbal working memory in non-affected siblings, independent of age. Conclusions. These results might indicate that the effect of the DRD4 7-repeat allele on neuropsychological functioning is dependent on age and ADHD status.

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