Absence of the 7‐repeat variant of the DRD4 VNTR is associated with drifting sustained attention in children with ADHD but not in controls

Many genetic studies have demonstrated an association between the 7‐repeat (7r) allele of a 48‐base pair variable number of tandem repeats (VNTR) in exon 3 of the DRD4 gene and the phenotype of attention deficit hyperactivity disorder (ADHD). Previous studies have shown inconsistent associations between the 7r allele and neurocognitive performance in children with ADHD. We investigated the performance of 128 children with and without ADHD on the Fixed and Random versions of the Sustained Attention to Response Task (SART). We employed time‐series analyses of reaction‐time data to allow a fine‐grained analysis of reaction time variability, a candidate endophenotype for ADHD. Children were grouped into either the 7r‐present group (possessing at least one copy of the 7r allele) or the 7r‐absent group. The ADHD group made significantly more commission errors and was significantly more variable in RT in terms of fast moment‐to‐moment variability than the control group, but no effect of genotype was found on these measures. Children with ADHD without the 7r allele made significantly more omission errors, were significantly more variable in the slow frequency domain and showed less sensitivity to the signal (d') than those children with ADHD the 7r and control children with or without the 7r. These results highlight the utility of time‐series analyses of reaction time data for delineating the neuropsychological deficits associated with ADHD and the DRD4 VNTR. Absence of the 7‐repeat allele in children with ADHD is associated with a neurocognitive profile of drifting sustained attention that gives rise to variable and inconsistent performance. © 2008 Wiley‐Liss, Inc.

[1]  J. Kuntsi,et al.  Psychological mechanisms in hyperactivity: II. The role of genetic factors. , 2001, Journal of child psychology and psychiatry, and allied disciplines.

[2]  J L Bradshaw,et al.  Fronto-parietal activation in attention-deficit hyperactivity disorder, combined type: functional magnetic resonance imaging study. , 2005, The British journal of psychiatry : the journal of mental science.

[3]  D. Cory-Slechta,et al.  Interactive Effects of a DRD4 Polymorphism, Lead, and Sex on Executive Functions in Children , 2007, Biological Psychiatry.

[4]  V. Pickel,et al.  Presynaptic dopamine D4 receptor localization in the rat nucleus accumbens shell , 2000, Synapse.

[5]  G. Hobbes,et al.  Does haloperidol block methylphenidate? , 1996, Psychopharmacology.

[6]  I. Robertson,et al.  `Oops!': Performance correlates of everyday attentional failures in traumatic brain injured and normal subjects , 1997, Neuropsychologia.

[7]  Sandra K Loo,et al.  Functional effects of the DAT1 polymorphism on EEG measures in ADHD. , 2003, Journal of the American Academy of Child and Adolescent Psychiatry.

[8]  R. Oades Differential measures of ‘sustained attention’ in children with attention-deficit/hyperactivity or tic disorders: relations to monoamine metabolism , 2000, Psychiatry Research.

[9]  M. Posner,et al.  Research on attention networks as a model for the integration of psychological science. , 2007, Annual review of psychology.

[10]  H. V. Van Tol,et al.  Modulation of Intracellular Cyclic AMP Levels by Different Human Dopamine D4 Receptor Variants , 1995, Journal of neurochemistry.

[11]  Katherine A. Johnson,et al.  Dissociation in performance of children with ADHD and high-functioning autism on a task of sustained attention , 2007, Neuropsychologia.

[12]  R. C. Oldfield The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[13]  K. Willmes,et al.  On the Functional Neuroanatomy of Intrinsic and Phasic Alertness , 2001, NeuroImage.

[14]  F. Rijsdijk,et al.  Reaction time, inhibition, working memory and ‘delay aversion’ performance: genetic influences and their interpretation , 2006, Psychological Medicine.

[15]  Katherine A. Johnson,et al.  Response variability in attention deficit hyperactivity disorder: evidence for neuropsychological heterogeneity. , 2007, Neuropsychologia.

[16]  K. Lesch,et al.  Dopamine and cognitive control: The influence of spontaneous eyeblink rate, DRD4 exon III polymorphism and gender on flexibility in set-shifting , 2007, Brain Research.

[17]  R. Ebstein,et al.  The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA) , 2002, Molecular Psychiatry.

[18]  Alan V. Oppenheim,et al.  Discrete-time Signal Processing. Vol.2 , 2001 .

[19]  J. Swanson,et al.  High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder , 2003, Molecular Psychiatry.

[20]  M I Posner,et al.  Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Gill,et al.  DRD4 gene variants and sustained attention in attention deficit hyperactivity disorder (ADHD): Effects of associated alleles at the VNTR and −521 SNP , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[22]  K. Starke,et al.  Presynaptic autoreceptors in the third decade: focus on alpha2-adrenoceptors. , 2001, Journal of neurochemistry.

[23]  A. Arnsten,et al.  Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions , 2004, Biological Psychiatry.

[24]  James Dermody,et al.  Dopamine receptor 4 (DRD4) 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetic study. , 2004, Journal of child and adolescent psychopharmacology.

[25]  S. Scott,et al.  Enhancing the Sensitivity of a Sustained Attention Task to Frontal Damage: Convergent Clinical and Functional Imaging Evidence , 2003, Neurocase.

[26]  H. V. Tol,et al.  The dopamine D4 receptors and mechanisms of antipsychotic atypicality , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[27]  D. Stuss,et al.  Staying on the job: the frontal lobes control individual performance variability. , 2003, Brain : a journal of neurology.

[28]  Bradford Navia,et al.  An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[29]  M. Owen,et al.  Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD. , 2004, The American journal of psychiatry.

[30]  B. Pennington,et al.  Validity of the Executive Function Theory of Attention-Deficit/Hyperactivity Disorder: A Meta-Analytic Review , 2005, Biological Psychiatry.

[31]  G. Gessa,et al.  Alpha2‐adrenoceptor mediated co‐release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex , 2004, Journal of neurochemistry.

[32]  P. Sham,et al.  Reaction time performance in ADHD: improvement under fast-incentive condition and familial effects , 2007, Psychological Medicine.

[33]  C. Conners Conners' rating scales-revised : technical manual , 1997 .

[34]  Dorret I Boomsma,et al.  Journal of Child Psychology and Psychiatry 45:2 (2004), pp 306–314 Familial in£uences on sustained attention and inhibition in preschoolers , 2022 .

[35]  J. Swanson,et al.  Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach , 1998, Molecular Psychiatry.

[36]  M. Bellgrove,et al.  The functional neuroanatomical correlates of response variability: evidence from a response inhibition task , 2004, Neuropsychologia.

[37]  K. Lesch,et al.  Dopamine and cognitive control: the influence of spontaneous eyeblink rate and dopamine gene polymorphisms on perseveration and distractibility. , 2005, Behavioral neuroscience.

[38]  Suzanne E. Welcome,et al.  Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder , 2003, The Lancet.

[39]  F. Castellanos,et al.  Varieties of Attention-Deficit/Hyperactivity Disorder-Related Intra-Individual Variability , 2005, Biological Psychiatry.

[40]  M. Posner,et al.  Assessing the molecular genetics of attention networks , 2002, BMC Neuroscience.

[41]  Eliza Congdon,et al.  Analysis of DRD4 and DAT polymorphisms and behavioral inhibition in healthy adults: Implications for impulsivity , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[42]  G. Aston-Jones,et al.  State-related activity, reactivity of locus ceruleus neurons in behaving monkeys. , 1998, Advances in pharmacology.

[43]  E J Costello,et al.  The Child and Adolescent Psychiatric Assessment (CAPA) , 1995, Psychological Medicine.

[44]  Neil A. Macmillan,et al.  Detection Theory: A User's Guide , 1991 .

[45]  Katherine A. Johnson,et al.  Dissociation in response to methylphenidate on response variability in a group of medication naïve children with ADHD , 2008, Neuropsychologia.

[46]  L. Snyder,et al.  Selective reconstitution of human D4 dopamine receptor variants with Gi alpha subtypes. , 2000, Biochemistry.

[47]  Lin He,et al.  Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). , 2006, Human molecular genetics.

[48]  J. Swanson,et al.  Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. , 1996, Molecular psychiatry.

[49]  C. Kieling,et al.  Association between DRD4 Gene and Performance of Children with ADHD in a Test of Sustained Attention , 2006, Biological Psychiatry.

[50]  No association of the dopamine DRD4 receptor (DRD4) gene polymorphism with attention deficit hyperactivity disorder (ADHD) in the Irish population. , 2000 .

[51]  F. Castellanos,et al.  Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes , 2002, Nature Reviews Neuroscience.