Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample

Association between attention-deficit hyperactivity disorder (ADHD) and the 10-repeat allele of the dopamine transporter gene (DAT1) has been reported in independent clinical samples using a categorical clinical definition of ADHD. The present study adopts a quantitative trait loci (QTL) approach to examine the association between DAT1 and a continuous measure of ADHD behaviours in a general-population sample, as well as to explore whether there is an independent association between DAT1 and performance on neuropsychological tests of attention, response inhibition, and working memory. From an epidemiological sample of 872 boys aged 6–11 years, we recruited 58 boys scoring above the 90th percentile for teacher reported ADHD symptoms (SWAN ADHD scale) and 68 boys scoring below 10th percentile for genotyping and neuropsychological testing. A significant association was found between the DAT1 homozygous 10/10-repeat genotype and high-scoring boys (χ2square=4.6, P<0.03; odds ratio=2.4, 95% CI 1.1–5.0). Using hierarchical linear regression, a significant independent association was found between the DAT1 10/10-repeat genotype and measures of selective attention and response inhibition after adjusting for age, IQ, and ADHD symptoms. There was no association between DAT1 and any component of working memory. Furthermore, performance on tasks of selective attention although associated with DAT1 was not associated with SWAN ADHD high scores after controlling for age and IQ. In contrast, impairment on tasks that tapped sustained attention and the central executive component of working memory were found in high-scoring boys after adjusting for age and IQ. The results suggest that DAT1 is a QTL for continuously distributed ADHD behaviours in the general population and the cognitive endophenotype of response inhibition.

[1]  M. Gill,et al.  Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children , 1999, Molecular Psychiatry.

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

[3]  S. Purcell,et al.  The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample , 2003, Molecular Psychiatry.

[4]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  L. Rohde,et al.  Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder. , 2002, Pharmacogenetics.

[6]  Tom Manly,et al.  Not enough time or not enough attention?: Speed, error and self- maintained control in the Sustained Attention to Response Test (SART). , 2000 .

[7]  A. Diamond,et al.  Genetic and neurochemical modulation of prefrontal cognitive functions in children. , 2004, The American journal of psychiatry.

[8]  J. Meere,et al.  Information Processing and Energetic Factors in Attention-Deficit/Hyperactivity Disorder , 1999 .

[9]  P. Asherson,et al.  No association between low- and high-activity catecholamine-methyl-transferase (COMT) and attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. , 2000, American journal of medical genetics.

[10]  J. Buitelaar,et al.  Deficient response inhibition as a cognitive endophenotype of ADHD. , 2003, Journal of the American Academy of Child and Adolescent Psychiatry.

[11]  S. Faraone,et al.  Family-environment risk factors for attention-deficit hyperactivity disorder. A test of Rutter's indicators of adversity. , 1995, Archives of general psychiatry.

[12]  M. Gill,et al.  Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism , 1997, Molecular Psychiatry.

[13]  Anthony M. Kang,et al.  Global variation of a 40-bp VNTR in the 3′-untranslated region of the dopamine transporter gene (SLC6A3) , 1999, Biological Psychiatry.

[14]  G. Logan,et al.  Effects of event rate and display time on sustained attention in hyperactive, normal, and control children , 1989, Journal of abnormal child psychology.

[15]  J. Epstein,et al.  Revision and Restandardization of the Conners Teacher Rating Scale (CTRS-R): Factor Structure, Reliability, and Criterion Validity , 1998, Journal of abnormal child psychology.

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

[17]  X Li,et al.  Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. , 1992, Genomics.

[18]  Jaap Oosterlaan,et al.  How specific is a deficit of executive functioning for Attention-Deficit/Hyperactivity Disorder? , 2002, Behavioural Brain Research.

[19]  M. Mcstephen,et al.  Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[20]  T. Shallice,et al.  Frontal lesions and sustained attention , 1987, Neuropsychologia.

[21]  J. Hirschhorn,et al.  A comprehensive review of genetic association studies , 2002, Genetics in Medicine.

[22]  S. Nelson,et al.  No evidence of linkage or linkage disequilibrium between DAT1 and attention deficit hyperactivity disorder in a large sample. , 1999, Psychiatric genetics.

[23]  M. Owen,et al.  A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder , 2000, Molecular Psychiatry.

[24]  E. Taylor,et al.  Neuropsychological analyses of impulsiveness in childhood hyperactivity , 2001, British Journal of Psychiatry.

[25]  J. Stevenson Evidence for a genetic etiology in hyperactivity in children , 1992, Behavior genetics.

[26]  Russell A. Barkley,et al.  Response inhibition in attention‐deficit hyperactivity disorder , 1999 .

[27]  C. Francks,et al.  A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. , 2002, American journal of human genetics.

[28]  V. Russell,et al.  A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes. , 2005, The Behavioral and brain sciences.

[29]  R. J. Mitchell,et al.  Distribution of the 3' VNTR polymorphism in the human dopamine transporter gene in world populations. , 2000, Human biology.

[30]  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.

[31]  U. Castiello,et al.  Neuropsychological Evaluation of Deficits in Executive Functioning for ADHD Children With or Without Learning Disabilities , 2002, Developmental neuropsychology.

[32]  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.

[33]  Yufei Wang,et al.  Prevalence of attention deficit hyperactivity disorder in primary school children in Taiwan. , 1993, Journal of the Formosan Medical Association = Taiwan yi zhi.

[34]  S. Gathercole,et al.  The Working Memory Test Battery for Children. , 2001 .

[35]  B. Madras,et al.  Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression , 2002, Molecular Psychiatry.

[36]  M. Snowling,et al.  Executive function and reading impairments in children reported by their teachers as ‘hyperactive’ , 2001 .

[37]  A. Malhotra,et al.  A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. , 2002, The American journal of psychiatry.

[38]  R. Schachar,et al.  Deficient inhibition as a marker for familial ADHD. , 2001, The American journal of psychiatry.

[39]  James D. A. Parker,et al.  The Revised Conners' Parent Rating Scale (CPRS-R): Factor Structure, Reliability, and Criterion Validity , 1998, Journal of abnormal child psychology.

[40]  James H. Johnson,et al.  The Test of Everyday Attention for Children (TEA-Ch): Patterns of Performance in Children With ADHD and Clinical Controls , 2001, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[41]  P. Maruff,et al.  Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children , 1999, Psychological Medicine.

[42]  P. McGuffin,et al.  Childhood hyperactivity scores are highly heritable and show sibling competition effects: Twin study evidence , 1995, Behavior genetics.

[43]  E. Sonuga-Barke,et al.  Psychological heterogeneity in AD/HD—a dual pathway model of behaviour and cognition , 2002, Behavioural Brain Research.

[44]  E. Sonuga-Barke,et al.  Are Planning, Working Memory, and Inhibition Associated With Individual Differences in Preschool ADHD Symptoms? , 2002, Developmental neuropsychology.

[45]  J. Oosterlaan,et al.  Psychological mechanisms in hyperactivity: I. Response inhibition deficit, working memory impairment, delay aversion, or something else? , 2001, Journal of child psychology and psychiatry, and allied disciplines.

[46]  J. Bacon-Shone,et al.  The Diagnosis and Prevalence of Hyperactivity in Chinese Schoolboys , 1996, British Journal of Psychiatry.

[47]  R. Elliott,et al.  Effects of methylphenidate on spatial working memory and planning in healthy young adults , 1997, Psychopharmacology.

[48]  K. Kerns,et al.  Time Reproduction, Working Memory, and Behavioral Inhibition in Children with ADHD , 2001, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[49]  A. Thapar,et al.  Genetic basis of attention deficit and hyperactivity , 1999, British Journal of Psychiatry.

[50]  B. Pennington,et al.  Attention deficit disorder in reading-disabled twins: Evidence for a genetic etiology , 1992, Journal of abnormal child psychology.

[51]  Herbert C. Quay,et al.  Handbook of disruptive behavior disorders , 1999 .

[52]  M. Gill,et al.  No association between catechol-O-methyltransferase (COMT) gene polymorphism and attention deficit hyperactivity disorder (ADHD) in an Irish sample. , 2000, American journal of medical genetics.

[53]  Katya Rubia,et al.  Evidence for a pure time perception deficit in children with ADHD. , 2002, Journal of child psychology and psychiatry, and allied disciplines.

[54]  H. Geurts,et al.  The top and the bottom of ADHD: a neuropsychological perspective , 2003, Neuroscience & Biobehavioral Reviews.

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

[56]  I. Nimmo-Smith,et al.  The differential assessment of children's attention: the Test of Everyday Attention for Children (TEA-Ch), normative sample and ADHD performance. , 2001, Journal of child psychology and psychiatry, and allied disciplines.

[57]  B. Pennington,et al.  Executive functions and developmental psychopathology. , 1996, Journal of child psychology and psychiatry, and allied disciplines.

[58]  W. Horn,et al.  Sex differences in school-aged children with pervasive attention deficit hyperactivity disorder , 1989, Journal of abnormal child psychology.

[59]  M. Nöthen,et al.  Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder , 2001, Biological Psychiatry.

[60]  S. Faraone,et al.  An exploratory study of ADHD among second-degree relatives of ADHD children , 1994, Biological Psychiatry.

[61]  J. Meere,et al.  Focused attention in pervasively hyperactive children , 1988, Journal of abnormal child psychology.

[62]  A. Heath,et al.  No association of the dopamine transporter gene 3' VNTR polymorphism with ADHD subtypes in a population sample of twins. , 2001, American journal of medical genetics.

[63]  R. Barkley Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. , 1997, Psychological bulletin.

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

[65]  I. Waldman,et al.  Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. , 1998, American journal of human genetics.

[66]  T. Sawaguchi,et al.  The effects of dopamine and its antagonists on directional delay-period activity of prefrontal neurons in monkeys during an oculomotor delayed-response task , 2001, Neuroscience Research.

[67]  G. Hynd,et al.  Neuropsychological development of behavior attributed to frontal lobe functioning in children , 1985 .

[68]  I. Nimmo-Smith,et al.  The structure of normal human attention: The Test of Everyday Attention , 1996, Journal of the International Neuropsychological Society.

[69]  A. Diamond,et al.  The relationship between cognition and action: performance of children 3 1 2 –7 years old on a stroop- like day-night test , 1994, Cognition.

[70]  L. Rohde,et al.  Attention-deficit hyperactivity disorder: a study of association with both the dopamine transporter gene and the dopamine D4 receptor gene. , 2001, American journal of medical genetics.

[71]  N J Cox,et al.  Association of attention-deficit disorder and the dopamine transporter gene. , 1995, American journal of human genetics.

[72]  B. Pennington,et al.  A comparison of the cognitive deficits in reading disability and attention-deficit/hyperactivity disorder. , 2001, Journal of abnormal psychology.

[73]  H. Feldman,et al.  Prevalence and assessment of attention-deficit/hyperactivity disorder in primary care settings. , 2001, Pediatrics.

[74]  J. Mill,et al.  Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples , 2001, Molecular Psychiatry.

[75]  G. Humphreys,et al.  Exploring selective attention in ADHD: visual search through space and time. , 2003, Journal of child psychology and psychiatry, and allied disciplines.

[76]  J. Nigg,et al.  Is ADHD a disinhibitory disorder? , 2001, Psychological bulletin.

[77]  S. Fuke,et al.  The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression , 2001, The Pharmacogenomics Journal.

[78]  R. Hu Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) , 2003 .

[79]  M. Raichle,et al.  Localization of a human system for sustained attention by positron emission tomography , 1991, Nature.

[80]  R. Ebstein,et al.  Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype. , 1999, American journal of medical genetics.

[81]  W. Roberts,et al.  Linkage study of catechol-O-methyltransferase and attention-deficit hyperactivity disorder. , 1999, American journal of medical genetics.

[82]  Jeanine J. Houwing-Duistermaat,et al.  Power of Selective Genotyping in Genetic Association Analyses of Quantitative Traits , 2000, Behavior genetics.

[83]  I. Craig,et al.  Expression of the dopamine transporter gene is regulated by the 3' UTR VNTR: Evidence from brain and lymphocytes using quantitative RT-PCR. , 2002, American journal of medical genetics.

[84]  H. Lou,et al.  Etiology and pathogenesis of Attention‐deficit Hyperactivity Disorder (ADHD): significance of prematurity and perinatal hypoxic‐haemodynamic encephalopathy , 1996, Acta paediatrica.

[85]  M. Caron,et al.  Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. , 1992, Molecular pharmacology.

[86]  S. Little,et al.  Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene. , 1992, American journal of human genetics.

[87]  J. Nigg,et al.  Continuous performance test in boys with attention deficit hyperactivity disorder: Methylphenidate does response and relations with observed behaviors , 1996 .

[88]  Wai Chen Attention, genes and ADHD , 2002 .