• Association betweenDRD2/DRD4interaction and conduct disorder: A potential developmental pathway to alcohol dependence

      Mota, Nina R.; Bau, Claiton H. D.; Banaschewski, Tobias; Buitelaar, Jan K.; Ebstein, Richard P.; Franke, Barbara; Gill, Michael; Kuntsi, Jonna; Manor, Iris; Miranda, Ana; et al. (Wiley, 2013-07-02)
    • Association of genetic risk severity with ADHD clinical characteristics

      Kotte, Amelia; Faraone, Stephen V.; Biederman, Joseph (Wiley, 2013-10-17)
      This study sought to examine the association between the cumulative risk severity conferred by the total number of attention-deficit/hyperactivity disorder (ADHD) risk alleles of the DAT1 3′UTR variable number tandem repeat (VNTR), DRD4 Exon 3 VNTR, and 5-HTTLPR with ADHD characteristics, clinical correlates, and functional outcomes in a pediatric sample. Participants were derived from case–control family studies of boys and girls diagnosed with ADHD, a genetic linkage study of families with children with ADHD, and a family genetic study of pediatric bipolar disorder. Caucasian children 18 and younger with and without ADHD and with available genetic data were included in this analysis (N = 591). The association of genetic risk severity with sociodemographic, clinical characteristics, neuropsychological, emotional, and behavioral correlates was examined in the entire sample, in the sample with ADHD, and in the sample without ADHD, respectively. Greater genetic risk severity was significantly associated with the presence of disruptive behavior disorders in the entire sample and oppositional defiant disorder in participants with ADHD. Greater genetic risk severity was also associated with the absence of anxiety disorders, specifically with the absence of agoraphobia in the context of ADHD. Additionally, one ADHD symptom was significantly associated with greater genetic risk severity. Genetic risk severity is significantly associated with ADHD clinical characteristics and co-morbid disorders, and the nature of these associations may vary on the type (externalizing vs. internalizing) of the disorder. © 2013 Wiley Periodicals, Inc.
    • Associations Between ADHD and Psychoactive Substance use Disorders:Findings from a Longitudinal Study of High-Risk Siblings of ADHD Children

      Milberger, Sharon; Biederman, Joseph; Faraone, Stephen V.; Wilens, Timothy; Chu, Monica P. (Wiley, 1997-01)
      The purpose of this study was to determine whether the single nucleotide polymorphisms (SNPs) within candidate genes for attention deficit hyperactivity disorder (ADHD) are associated with the age at onset for ADHD. One hundred and forty-three SNPs were genotyped across five candidate genes (DRD5, SLC6A3, HTR1B, SNAP25, DRD4) for ADHD in 229 families with at least one affected offspring. SNPs with the highest estimated power to detect an association with age at onset were selected for each candidate gene, using a power-based screening procedure that does not compromise the nominal significance level. A time-to-onset analysis for family-based samples was performed on these SNPs to determine if an association exists with age at onset for ADHD. Seven consecutive SNPs surrounding the D5 dopamine receptor gene (DRD5), were associated with the age at onset for ADHD; FDR adjusted q-values ranged from 0.008 to 0.023. This analysis indicates that individuals with the risk genotype develop ADHD earlier than individuals with any other genotype. A haplotype analysis across the 6 significant SNPs that were in linkage disequilibrium with one another, CTCATA, was also found to be significant (p-value = 0.02). We did not observe significant associations with age at onset for the other candidate loci tested. Although definitive conclusions await independent replication, these results suggest that a variant in DRD5 may affect age at onset for ADHD
    • Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome

      Thompson, Carlie A.; Karelis, Jason; Middleton, Frank A.; Gentile, Karen; Coman, Ioana L.; Radoeva, Petya D.; Mehta, Rashi; Fremont, Wanda P.; Antshel, Kevin M.; Faraone, Stephen V.; et al. (Wiley, 2017-01-31)
      22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with 22q11.2DS develop schizophrenia, though little is known about the underlying mechanisms. We hypothesized that allelic variation in functional polymorphisms in seven genes unique to the deleted region would affect lobar brain volumes, which would predict risk for psychosis in youth with 22q11.2DS. Participants included 56 individuals (30 males) with 22q11.2DS. Anatomic MR images were collected and processed using Freesurfer. Participants were genotyped for 10 SNPs in the COMT, DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms of psychosis. Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. Our results suggest that RTN4R, a relatively under-studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain. © 2017 Wiley Periodicals, Inc.
    • Autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in attention-deficit/hyperactivity disorder

      Hess, Jonathan L.; Radonjić, Nevena V.; Patak, Jameson; Glatt, Stephen J.; Faraone, Stephen V. (Springer Science and Business Media LLC, 2020-12-18)
      Large-scale brain imaging studies by the ENIGMA Consortium identified structural changes associated with attentiondeficit/ hyperactivity disorder (ADHD). It is not clear why some brain regions are impaired and others spared by the etiological risks for ADHD. We hypothesized that spatial variation in brain cell organization and/or pathway expression levels contribute to selective brain region vulnerability (SBRV) in ADHD. In this study, we used the largest available collection of magnetic resonance imaging (MRI) results from the ADHD ENIGMA Consortium (subcortical MRI n = 3242; cortical MRI n = 4180) along with high-resolution postmortem brain microarray data from Allen Brain Atlas (donors n = 6) from 22 brain regions to investigate our SBRV hypothesis. We performed deconvolution of the bulk transcriptomic data to determine abundances of neuronal and nonneuronal cells in the brain. We assessed the relationships between gene-set expression levels, cell abundance, and standardized effect sizes representing regional changes in brain sizes in cases of ADHD. Our analysis yielded significant correlations between apoptosis, autophagy, and neurodevelopment genes with smaller brain sizes in ADHD, along with associations to regional abundances of astrocytes and oligodendrocytes. The lack of enrichment of common genetic risk variants for ADHD within implicated gene sets suggests an environmental etiology to these differences. This work provides novel mechanistic clues about SBRV in ADHD.
    • Bipolar and antisocial disorders among relatives of ADHD children: parsing familial subtypes of illness

      Faraone, Stephen V.; Biederman, Joseph; Mennin, Douglas; Russell, Ronald (Wiley, 1998-02-07)
      Attention deficit hyperactivity disorder (ADHD) is a familial disorder that is highly comorbid with conduct disorder and sometimes co-occurs with bipolar disorder. This pattern of comorbidity is also seen among relatives of ADHD probands. A growing literature suggests that ADHD with antisocial comorbidity may be nosologically distinct from other forms of ADHD. A similar pattern has been observed for ADHD and bipolar disorder. Given these results, along with the observed comorbidity between conduct and bipolar disorders, we used data from our study of 140 ADHD and 120 control families to determine if conduct and bipolar disorders in ADHD boys should be considered alternative manifestations of the same familial disorder. The probands and their relatives were examined with DSM-III-R structured diagnostic interviews and were assessed for cognitive, achievement, social, school, and family functioning. Our results provide fairly consistent support for the hypothesis that antisocial- and bipolar-ADHD subtypes are different manifestations of the same familial condition. As predicted by this hypothesis, there was a significant three-way association between variables assessing the family history of each disorder. Moreover, when families were stratified into bipolar, antisocial, and other types, few differences emerged between the bipolar and antisocial families. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:108–116, 1998. © 1998 Wiley-Liss, Inc.
    • 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.
    • CAG-Repeat length in exon 1 of KCNN3 does not influence risk for schizophrenia or bipolar disorder: A meta-analysis of association studies

      Glatt, Stephen J.; Faraone, Stephen V.; Tsuang, Ming T. (Wiley, 2003-07-30)
      Schizophrenia and bipolar disorder both showsomeevidence for genetic anticipation. In addition, significant expansion of anonymous CAG repeats throughout the genome has been detected in both of these disorders. The gene KCNN3, which codes for a small/ intermediate conductance, calcium-regulated potassium channel, contains a highly polymorphic CAG-repeat array in exon 1. Initial evidence for association of both schizophrenia and bipolar disorder with increased CAG-repeat length of KCNN3 has not been consistently replicated. In the present study, we performed several metaanalyses to evaluate the pooled evidence for association with CAG-repeat length of KCNN3 derived from case-control and family-based studies of both disorders. Each group of studies was analyzed under two models, including a test for direct association with repeat length, and a test for association with dichotomized repeat-length groups. No evidence for a linear relationship between disease risk and repeat length was observed, as all pooled odds ratios approximated 1.0. Results of dichotomized allelegroup analyses were more variable, especially for schizophrenia, where case-control studies found a significant association with longer repeats but family-based studies implicated shorter alleles. The results of these meta-analyses demonstrate that the risks for both schizophrenia and bipolar disorder are largely, if not entirely, independent of CAG-repeat length in exon 1 of KCNN3. This study cannot exclude the possibility that some aspect of this polymorphism, such as repeat-length disparity in heterozygotes, influences risk for these disorders. Further, it remains unknown if this polymorphism, or one in linkage disequilibrium with it, contributes to some distinct feature of the disorder, such as symptom severity or anticipation.
    • Can sodium/hydrogen exchange inhibitors be repositioned for treating attention deficit hyperactivity disorder? An in silico approach

      Faraone, Stephen V.; Zhang-James, Yanli (Wiley, 2013-10-17)
      Medications for attention deficit hyperactivity disorder (ADHD) are only partially effective. Ideally, new treatment targets would derive from a known pathophysiology. Such data are not available for ADHD. We combine evidence for new etiologic pathways with bioinformatics data to assess the possibility that existing drugs might be repositioning for treating ADHD. We use this approach to determine if prior data implicating the sodium/hydrogen exchanger 9 gene (SLC9A9) in ADHD implicate sodium/hydrogen exchange (NHE) inhibitors as potential treatments. We assessed the potential for repositioning by assessing the similarity of drug–protein binding profiles between NHE inhibitors and drugs known to treat ADHD using the Drug Repositioning and Adverse Reaction via Chemical–Protein Interactome server. NHE9 shows a high degree of amino acid similarity between NHE inhibitor sensitive NHEs in the region of the NHE inhibitor recognition site defined for NHE1. We found high correlations in drug–protein binding profiles among most ADHD drugs. The drug–protein binding profiles of some NHE inhibitors were highly correlated with ADHD drugs whereas the profiles for a control set of nonsteroidal anti-inflammatory drugs (NSAIDs) were not. Further experimental work should evaluate if NHE inhibitors are suitable for treating ADHD. © 2013 Wiley Periodicals, Inc.
    • Characteristics of Adults with Attention Deficit Hyperactivity Disorder Plus Substance Use Disorder: The Role of Psychiatric Comorbidity

      Wilens, Timothy E.; Kwon, Anne; Tanguay, Sarah; Chase, Rhea; Moore, Hadley; Faraone, Stephen V.; Biederman, Joseph (Wiley, 2005-01)
      The objective of the study was to investigate the characteristics of adults with Attention Deficit Hyperactivity Disorder (ADHD) or substance use disorder (SUD), especially in the context of comorbid psychiatric disorders. Subjects were adults (n ¼ 78) participating in a controlled family study of ADHD and SUD. Four groups were identified based on a diagnosis of ADHD or SUD: ADHD, SUD, ADHDþSUD, and neither ADHD nor SUD. All diagnoses were determined by structured clinical interview for DSM IV. Rates of psychiatric comorbidity were lowest in the controls, intermediate in the ADHD and SUD groups, and highest in the ADHDþSUD group. Relative to controls, the ADHD, SUD, and ADHDþSUD groups had higher rates of major depression (z ¼ 1.98, p ¼ 0.05), conduct disorder (z ¼ 2.0, p ¼ 0.04), antisocial personality disorder (z ¼ 2.6, p ¼ 0.009), agoraphobia (z ¼ 2.5, p ¼ 0.01) and social phobia (z ¼ 2.7, p ¼ 0.007). Higher rates of psychiatric comorbidity, especially mood and anxiety disorders, exist in subjects with SUDþADHD relative to subjects with SUD, ADHD, or controls. Clinicians need to be attentive to other psychiatric disorders that may occur in the large group of adults with ADHDþSUD.
    • Comorbidity of ADHD and adult bipolar disorder: A systematic review and meta-analysis

      Schiweck, Carmen; Arteaga-Henriquez, Gara; Aichholzer, Mareike; Edwin Thanarajah, Sharmili; Vargas-Cáceres, Sebastian; Matura, Silke; Grimm, Oliver; Haavik, Jan; Kittel-Schneider, Sarah; Ramos-Quiroga, Josep Antoni; et al. (Elsevier BV, 2021-05)
      Attention-deficit / hyperactivity disorder (ADHD) and Bipolar Disorder (BD) are common mental disorders with a high degree of comorbidity. However, no systematic review with meta-analysis has aimed to quantify the degree of comorbidity between both disorders. To this end we performed a systematic search of the literature in October 2020. In a meta-analysis of 71 studies with 646,766 participants from 18 countries, it was found that about one in thirteen adults with ADHD was also diagnosed with BD (7.95 %; 95 % CI: 5.31-11.06), and nearly one in six adults with BD had ADHD (17.11 %; 95 % CI: 13.05-21.59 %). Substantial heterogeneity of comorbidity rates was present, highlighting the importance of contextual factors: Heterogeneity could partially be explained by diagnostic system, sample size and geographical location. Age of BD onset occurred earlier in patients with comorbid ADHD (3.96 years; 95 % CI: 2.65-5.26, p < 0.001). Cultural and methodological differences deserve attention for evaluating diagnostic criteria and clinicians should be aware of the high comorbidity rates to prevent misdiagnosis and provide optimal care for both disorders.
    • The concept of target features in schizophrenia research

      Tsuang, M. T.; Faraone, Stephen V. (Wiley, 1999-05)
      Target features are clinical or neurobiological characteristics that arc expressions of the underlying predisposition to an illness. They comprise a wide range of phenomena, from thc classic signs and symptoms of psychopathology to sophisticated measures of brain structure and function. For schizophrenia, many target features have been identified. These include eye tracking dysfunction, attentional impairment, allusive thinking, neurological signs, thought disorder, characteristic auditory evoked potentials, neuropsychological impairment, structural brain abnormalities and functional brain abnormalities. In their most pathological forms, thcse features are present among many schizophrenic patients, yet it is their presence among their non-psychotic relatives that shows them to be target features. We discuss the theoretical background for target features, present examples and describe how the discovery of target features has implications I for schizophrenia research.
    • Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure

      Hoogman, Martine; Rooij, Daan; Klein, Marieke; Boedhoe, Premika; Ilioska, Iva; Li, Ting; Patel, Yash; Postema, Merel C.; Zhang‐James, Yanli; Anagnostou, Evdokia; et al. (Wiley, 2020-05-18)
      Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
    • A Controlled Study of Behavioral Inhibition in Children of Parents With Panic Disorder and Depression

      Rosenbaum, Jerrold F.; Biederman, Joseph; Hirshfeld-Becker, Dina R.; Kagan, Jerome; Snidman, Nancy; Friedman, Deborah; Nineberg, Allan; Gallery, Daniel J.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2000-12)
      Objective: “Behavioral inhibition to the unfamiliar” has been proposed as a precursor to anxiety disorders. Children with behavioral inhibition are cautious, quiet, introverted, and shy in unfamiliar situations. Several lines of evidence suggest that behavioral inhibition is an index of anxiety proneness. The authors sought to replicate prior findings and examine the specificity of the association between behavioral inhibition and anxiety. Method: Laboratory-based behavioral observations were used to assess behavioral inhibition in 129 young children of parents with panic disorder and major depression, 22 children of parents with panic disorder without major depression, 49 children of parents with major depression without panic disorder, and 84 children of parents without anxiety disorders or major depression (comparison group). A standard definition of behavioral inhibition based on previous research (“dichotomous behavioral inhibition”) was compared with two other definitions. Results: Dichotomous behavioral inhibition was most frequent among the children of parents with panic disorder plus major depression (29% versus 12% in comparison subjects). For all definitions, the univariate effects of parental major depression were significant (conferring a twofold risk for behavioral inhibition), and for most definitions the effects of parental panic disorder conferred a twofold risk as well. Conclusions: These results suggest that the comorbidity of panic disorder and major depression accounts for much of the observed familial link between parental panic disorder and childhood behavioral inhibition. Further work is needed to elucidate the role of parental major depression in conferring risk for behavioral inhibition in children.
    • 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.
    • Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family

      Myles-Worsley, Marina; Tiobech, Josepha; Browning, Sharon R.; Korn, Jeremy; Goodman, Sarah; Gentile, Karen; Melhem, Nadine; Byerley, William; Faraone, Stephen V.; Middleton, Frank A. (Wiley, 2013-01-22)
      Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three “obligate-carrier” parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na2+/dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. © 2013 Wiley Periodicals, Inc.
    • Differential Effect of Environmental Adversity by Gender: Rutter’s Index of Adversity in a Group of Boys and Girls With and Without ADHD

      Biederman, Joseph; Faraone, Stephen V.; Monuteaux, Michael C. (American Psychiatric Association Publishing, 2002-09)
      Objective: This study examined the effect of gender in mediating the association between environmental adversity and the risk of attention deficit hyperactivity disorder (ADHD) and associated impairments. Method: The authors studied 280 ADHD and 242 healthy comparison probands of both genders who were between the ages of 6 and 17 years. They tested the association between Rutter’s indicators of adversity (including family conflict, social class, family size, maternal psychopathology, and paternal criminality) and ADHD, comorbidity, and functioning. Results: Greater levels of environmental adversity were associated with a greater risk for ADHD and other comorbidity in both genders in a dose-dependent fashion. However, learning disability and global functioning were modified by gender, with more detrimental effects observed in boys than in girls. Low social class, maternal psychopathology, and family conflict were significantly associated with psychopathology and functional impairment in the probands, with control for gender, parental ADHD, proband ADHD status, and maternal smoking during pregnancy. Conclusions: Psychosocial adversity in general and low social class, maternal psychopathology, and family conflict in particular increased the risk for ADHD and associated morbidity independently of gender and other risk factors, but gender modified the risk for adverse cognitive and interpersonal outcomes; boys were more vulnerable to the disorder than girls. Because of the difficulties in separating the effects of genetics from environment, these results must be interpreted as provisional until confirmation from twin and adoption studies.
    • Disorder Versus Disability: The Challenge of ADHD in the Context of a High IQ

      Antshel, Kevin M.; Hendricks, Kaitlin; Faraone, Stephen V.; Gordon, Michael (Guilford Publications, 2011-04)
    • Dopamine D4 Gene 7-Repeat Allele and Attention Deficit Hyperactivity Disorder

      Faraone, Stephen V.; Biederman, Joseph; Weiffenbach, Barbara; Keith, Tim; Chu, Monica P.; Weaver, Alix; Spencer, Thomas J.; Wilens, Timothy E.; Frazier, Jean; Cleves, Mario; et al. (American Journal of Psychiatry, 1999-05)
      Objective: Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component, and some studies have reported an association between ADHD and the dopamine D4 (DRD4) gene. Method: The authors recruited 27 triads that comprised an ADHD adult, his or her spouse, and their ADHD child. These triads were assessed for ADHD, and their DNA was genotyped for DRD4 alleles. Results: A multiallelic transmission disequilibrium test suggested an association between ADHD and the DRD4 7-repeat allele. Among family members, the number of 7-repeat alleles predicted the diagnosis of ADHD. Conclusions: Prior reports of an association between ADHD and DRD4 generalize to families recruited through clinically referred ADHD adults. However, because there are some conflicting studies, further work is needed to clarify the role of DRD4 in the etiology of the disorder.
    • 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.